Vitamin D derivatives with C-25 substituents, process for their preparation, intermediate products and their use in preparing medicaments

ABSTRACT

A vitamin D derivative and its uses with substituents at C-25 of general formula I

This application is a 371 of PCT/EP96/01788 filed Apr. 30, 1996.

This invention relates to vitamin D derivatives with substituents atC-25 of general formula I

in which

Y₁ means a hydrogen atom, a hydroxyl group, an alkanoyloxy group with 1to 12 C atoms or an aroyloxy group,

Y₂ means a hydrogen atom or an alkanoyl group with 1 to 12 C atoms or anaroyl group,

R₁ and R₂ each mean a hydrogen atom or together an exocyclic methylenegroup,

R₃ and R₄, independently of one another, mean a hydrogen atom, achlorine or fluorine atom, an alkyl group with 1 to 4 carbon atoms,together a methylene group or together with quaternary carbon atom 20 a3- to 7-membered, saturated or unsaturated carbocyclic ring,

A and B together mean a keto group or A means a group OR′ and B means ahydrogen atom or B means a group OR′ and A means a hydrogen atom,whereby R′ is a hydrogen atom or a straight-chain or branched-chain,saturated alkanoyl group with up to 9 carbon atoms or an aroyl group,

R₅ and R₆ at the same time each mean a hydrogen atom, a chlorine orfluorine atom, a trifluoromethyl group, a straight-chain orbranched-chain, saturated or unsaturated hydrocarbon radical with up to4 carbon atoms or R₅ and R₆ together with carbon atom 25 mean a 3- to7-membered, saturated or unsaturated carbocyclic ring and

Z means a straight-chain or branched-chain, saturated or unsaturatedhydrocarbon radical with up to 12 carbon atoms, which can also have acarbocyclic or heterocyclic partial structure and at any positions canexhibit keto groups, hydroxy groups (in α- or β-position) that in turncan be etherified or esterified, amino groups, halogen atoms orcarboxylic acid ester or amide units and is linked by a carbonyl group,a hydroxymethylene group or an ethenediyl unit C—CH═CH—, E- orZ-geometry) with carbon atom 25,

and processes for their production, intermediate products for theseprocesses, pharmaceutical preparations that contain these compounds aswell as their use for the production of pharmaceutical agents.

The alkanoyl or alkanoyloxy groups with 1 to 12 C atoms that arepossible for radicals Y₁ and Y₂ are derived especially from saturatedcarboxylic acids. These radicals can be cyclic, acyclic, carbocyclic orheterocyclic. The preferred radicals are derived from C₁ to C₉,especially C₂ to C₅ alkanecarboxylic acids, such as, for example,acetyl(oxy), propionyl(oxy), butyryl(oxy).

As aroyl(oxy) groups, the benzoyl(oxy) groups and substitutedbenzoyl(oxy) groups are preferred.

For R₃ and R₄, the following preferred combinations apply: R₃=H,R₄=methyl or R₃=methyl, R₄=H; R₃=F, R₄=methyl or R₃=methyl, R₄=F; R₃,R₄=methyl; R₃ and R₄ together form a methylene group or together withtertiary carbon atom 20 form a cyclopropyl ring.

For A and B, the following preferred combinations apply:

A=OH, B=H or A=H, B=OH and A and B form a carbonyl group.

For R₅ and R₆, the following preferred combinations apply:

R₅, R₆=methyl or ethyl; R₅ and R₆ together with carbon atom 25 form acyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring.

Especially preferred are the cases R₅, R₆=methyl, and R₅ and R₆ togetherwith carbon atom 25 form a cyclopropyl ring.

For Z, the following preferences apply:

Z=—C(O)—R₉ or Z=—CH(OH)—R₉ (α- or β-hydroxy), whereby R₉ is astraight-chain or branched-chain, saturated or unsaturated hydrocarbonradical with up to 12 carbon atoms or else R₉ can be carbocyclic orheterocyclic or can exhibit such partial structures and can also beperfluorinated.

For R₉, the following special preferences apply:

R₉=methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, i-propyl,i-butyl, t-butyl, 1-butenyl, 1-pentenyl, 1-butinyl, 1-pentinyl, phenyl,furanyl, pyridinyl, trifluoromethyl, perfluoroethyl, perfluoropropyl,perfluorobutyl, perfluoropentyl or perfluorohexyl.

Also, for Z, the following preference applies:

with R₁₂=C₁-C₁₀ alkyl or alkoxy (straight-chain, branched, saturated,unsaturated, cyclic) or

with R₁₃=C₁-C₁₀ alkyl (straight-chain, branched, saturated, unsaturated,cyclic), whereby R₁₃ can also have substituents (keto groups, hydroxygroups, carboxylic acid esters, carboxylic acid amides, halogens).

Especially preferred according to this invention are the followingcompounds:

(5Z,7E,22E)-(1S,3R,24R)-25-(1-Oxopentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-25-(1-oxopentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24R)-25-acetyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-25-acetyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24R)-25-(1-oxopropyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-25-(1-oxopropyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24R)-25-(1-oxobutyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-25-(1-oxobutyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24R)-25-(1-oxohexyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-25-(1-oxohexyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24R)-25-(1-oxoheptyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-25-(1-oxoheptyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24R)-25-(1-oxooctyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-25-(1-oxooctyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24R)-25-(1-oxononyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-25-(1-oxononyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24R)-25-benzoyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-25-benzoyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24R)-25-(2-furanylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-25-(2-furanylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24R)-25-(2,2-dimethyl-1-oxopropyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-25-(2,2-dimethyl-1-oxopropyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24R)-25-(2-pyridinylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-25-(2-pyridinylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-(1-oxo-2-hexenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

[5Z,7E,22E,25(E)]-(1S,3R,24S)-25-(1-oxo-2-hexenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24R)-25-(1-oxo-2-hexenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-25-(1-oxo-2-hexinyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24R)-25-(cyclopropylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-25-(cyclopropylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-(3-ethoxy-3-oxo-1-propenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

[5Z,7E,22E,25(E)]-(1S,3R,24S)-25-(3-ethoxy-3-oxo-1-propenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-[3-(1,1-dimethylethoxy)-3-oxo-1-propenyl]-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

[5Z,7E,22E,25(E)]-(1S,3R,24S)-25-[3-(1,1-dimethylethoxy)-3-oxo-1-propenyl]-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-(3-propoxy-3-oxo-1-propenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

[5Z,7E,22E,25(E)]-(1S,3R,24S)-25-(3-propoxy-3-oxo-1-propenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-(3-butoxy-3-oxo-1-propenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

[5Z,7E,22E,25(E)]-(1S,3R,24S)-25-(3-butoxy-3-oxo-1-propenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-[1S,3R,24S,25(S)]-25-(1-hydroxy-2,2,3,3,4,4,5,5,5-nonafluoropentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-[1S,3R,24S,25(R)]-25-(1-hydroxy-2,2,3,3,4,4,5,5,5-nonafluoropentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-[1S,3R,24R,25(S)]-25-(1-hydroxy-2,2,3,3,4,4,5,5,5-nonafluoropentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-[1S,3R,24R,25(R)]-25-(1-hydroxy-2,2,3,3,4,4,5,5,5-nonafluoropentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-[1S,3R,24S,25(S)]-25-(1-hydroxy-2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoroheptyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-[1S,3R,24S,25(R)]-25-(1-hydroxy-2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoroheptyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-[1S,3R,24R,25(S)]-25-(1-hydroxy-2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoroheptyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-[1S,3R,24R,25(R)]-25-(1-hydroxy-2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoroheptyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24R)-25-(trifluoroacetyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-25-(trifluoroacetyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24R)-25-(perfluoroethylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-25-(perfluoroethylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24R)-25-(perfluoropropylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-25-(perfluoropropylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24R)-25-(perfluorobutylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-25-(perfluorobutylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24R)-25-(perfluoropentylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-25-(perfluoropentylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24R)-25-(perfluorohexylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-25-(perfluorohexylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24R)-25-acetyl-20-methyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-25-acetyl-20-methyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24R)-20-methyl-25-(1-oxopropyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-20-methyl-25-(1-oxopropyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24R)-20-methyl-25-(1-oxobutyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-20-methyl-25-(1-oxobutyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24R)-20-methyl-25-(1-oxopentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-20-methyl-25-(1-oxopentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24R)-20-methyl-25-(1-oxohexyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-20-methyl-25-(1-oxohexyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24R)-20-methyl-25-(1-oxoheptyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-20-methyl-25-(1-oxoheptyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24R)-20-methyl-25-(1-oxooctyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-20-methyl-25-(1-oxooctyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24R)-20-methyl-25-(1-oxononyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-20-methyl-25-(1-oxononyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(7E,22E)-(1R,3R,24R)-25-acetyl-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol

(7E,22E)-(1R,3R,24S)-25-acetyl-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol

(7E,22E)-(1R,3R,24R)-25-(1-oxopropyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol

(7E,22E)-(1R,3R,24S)-25-(1-oxopropyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol

(7E,22E)-(1R,3R,24R)-25-(1-oxobutyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol

(7E,22E)-(1R,3R,24S)-25-(1-oxobutyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol

(7E,22E)-(1R,3R,24R)-25-(1-oxopentyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol

(7E,22E)-(1R,3R,24S)-25-(1-oxopentyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol

(7E,22E)-(1R,3R,24R)-25-(1-oxohexyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol

(7E,22E)-(1R,3R,24S)-25-(1-oxohexyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol

(7E,22E)-(1R,3R,24R)-25-(1-oxoheptyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol

(7E,22E)-(1R,3R,24S)-25-(1-oxoheptyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol

(7E,22E)-(1R,3R,24R)-25-(1-oxooctyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol

(7E,22E)-(1R,3R,24S)-25-(1-oxooctyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol

(7E,22E)-(1R,3R,24R)-25-(1-oxononyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol

(7E,22E)-(1R,3R,24S)-25-(1-oxononyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol

(7E,22E)-(1R,3R,24R)-25-acetyl-20-methyl-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol

(7E,22E)-(1R,3R,24S)-25-acetyl-20-methyl-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol

(7E,22E)-(1R,3R,24R)-20-methyl-25-(1-oxopropyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol

(7E,22E)-(1R,3R,24S)-20-methyl-25-(1-oxopropyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol

(7E,22E)-(1R,3R,24R)-20-methyl-25-(1-oxobutyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol

(7E,22E)-(1R,3R,24S)-20-methyl-25-(1-oxobutyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol

(7E,22E)-(1R,3R,24R)-20-methyl-25-(1-oxopentyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol

(7E,22E)-(1R,3R,24S)-20-methyl-25-(1-oxopentyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol

(7E,22E)-(1R,3R,24R)-20-methyl-25-(1-oxohexyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol

(7E,22E)-(1R,3R,24S)-20-methyl-25-(1-oxohexyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol

(7E,22E)-(1R,3R,24R)-20-methyl-25-(1-oxoheptyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol

(7E,22E)-(1R,3R,24S)-20-methyl-25-(1-oxoheptyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol

(7E,22E)-(1R,3R,24R)-20-methyl-25-(1-oxooctyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol

(7E,22E)-(1R,3R,24S)-20-methyl-25-(1-oxooctyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol

(7E,22E)-(1R,3R,24R)-20-methyl-25-(1-oxononyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol

(7E,22E)-(1R,3R,24S)-20-methyl-25-(1-oxononyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,25(R)]-1,3-dihydroxy-25-(1-hydroxy-2,2,3,3,4,4,5,5,5-nonafluoropentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen-24-one

(5Z,7E,22E)-(1S,3R,25(S)]-1,3-dihydroxy-25-(1-hydroxy-2,2,3,3,4,4,5,5,5-nonafluoropentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen-24-one

(5Z,7E,22E)-[1S,3R,25(R)]-1,3-dihydroxy-25-(1-hydroxy-2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoroheptyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen-24-one

(5Z,7E,22E)-[1S,3R,25(S)]-1,3-dihydroxy-25-(1-hydroxy-2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoroheptyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen-24-one

(5Z,7E,22E)-(3S,24R)-25-acetyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol

(5Z,7E,22E)-(3S,24S)-25-acetyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol

(5Z,7E,22E)-(3S,24R)-25-(1-oxopropyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol

(5Z,7E,22E)-(3S,24S)-25-(1-oxopropyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol

(5Z,7E,22E)-(3S,24R)-25-(1-oxobutyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol

(5Z,7E,22E)-(3S,24S)-25-(1-oxobutyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol

(5Z,7E,22E)-(3S,24R)-25-(1-oxopentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol

(5Z,7E,22E)-(3S,24S)-25-(1-oxopentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol

(5Z,7E,22E)-(3S,24R)-25-(1-oxohexyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol

(5Z,7E,22E)-(3S,24S)-25-(1-oxohexyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol

(5Z,7E,22E)-(3S,24R)-25-(1-oxoheptyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol

(5Z,7E,22E)-(3S,24S)-25-(1-oxoheptyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol

(5Z,7E,22E)-(3S,24R)-25-(1-oxooctyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol

(5Z,7E,22E)-(3S,24S)-25-(1-oxooctyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol

(5Z,7E,22E)-(3S,24R)-25-(1-oxononyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol

(5Z,7E,22E)-(3S,24S)-25-(1-oxononyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol

[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-[3-(1,1-dimethylethoxy)-3-oxo-1-propenyl]-24-methoxy-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3diol

[5Z,7E,22E,25(E)]-(1S,3R,24S)-25-[3-(1,1-dimethylethoxy)-3-oxo-1-propenyl]-24-methoxy-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3diol

(5Z,7E,22E)-(1S,3R,24R)-25-hydroxymethyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

(5Z,7E,22E)-(1S,3R,24S)-25-hydroxymethyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-(3-oxo-1-heptenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

[5Z,7E,22E,25(E)]-(1S,3R,24S)-25-(3-oxo-1-heptenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

[5Z,7E,22E,25(E,E)]-(1S,3R,24R)-25-(1-oxo-2,4-hexadienyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

[5Z,7E,22E,25(E,E)]-(1S,3R,24S)-25-(1-oxo-2,4-hexadienyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

The natural vitamins D₂ and D₃ (cf. general formula of vitamin D) areinherently biologically inactive and are converted into biologicallyactive metabolites [1α,25-dihydroxy vitamin D₃ (calcitriol) or -D₂] onlyafter hydroxylation at C-atom 25 in the liver and at C-atom 1 in thekidney. The action of the active metabolites involves the regulation ofthe calcium and phosphate concentration in the serum; they counteract adropping of the calcium concentration in the serum by increasing thecalcium absorption in the intestine and under certain circumstancespromoting calcium mobilization from the bones.

In addition to their pronounced effect on the calcium and phosphatemetabolism, the active metabolites of vitamins D₂ and D₃ and theirsynthetic derivatives have a proliferation-inhibiting anddifferentiation-stimulating action on tumor cells and normal cells, suchas, for example, skin cells. In addition, a pronounced effect on cellsof the immune system (inhibiting of proliferation and interleukin2-synthesis of lymphocytes, increase of cytotoxicity and phagocytosis invitro of monocytes) has been found, which manifests itself in animmunomodulatory action, and finally, because of a stimulating action onbone-forming cells, an increased formation of bone in normal andosteoporotic rats is found [R. Bouillon et al. “Short Term Course of1,25(OH)₂D₃ Stimulates Osteoblasts But Not Osteoclasts.” Calc. TissueInt. 49, 168-173 (1991)].

All actions are mediated by bonding to the vitamin D receptor. Becauseof the bonding, the activity of specific genes is regulated.

When using biologically active metabolites of vitamins D₂ and D₃, atoxic effect on the calcium metabolism is produced (hypercalcemia).

By structural manipulations of the side chain, therapeutically usableeffectiveness can be separated from undesirable hypercalcemic activity.A suitable structural variation is the introduction of 24-hydroxyderivatives.

1α-Cholecalciferols that are hydroxylated in 24-position are alreadydescribed in DE 25 26 981. They have a lower toxicity than thecorresponding non-hydroxylated 1α-cholecalciferol. Further, 24-hydroxyderivatives are described in the following patent applications: DE 39 33034, DE 40 03 854, DE 40 34 730, EP 0 421 561, EP 0 441 467, WO91/12238.

Finally, 25-carboxylic acid derivatives of calcitriol that arehydroxylated at C-24 are described in WO 94/07853, which exhibit a moreadvantageous spectrum of action than calcitriol. While the ability totrigger a hypercalcemia is considerably weakened, theproliferation-inhibiting and differentiation-stimulating actions aremaintained.

Relative to these structurally allied compounds, the substancesaccording to the invention are distinguished in that they show a greatereffect on cell differentiation, whereby the effect on the calciumbalance does not increase.

The vitamin D activity of the substances according to the invention isdetermined with the aid of the calcitriol-receptor test. It is carriedout with use of a specific receptor protein from the intestines ofjuvenile pigs.

Receptor-containing binding protein is incubated in a test tube with³H-calcitriol (5×10⁻¹⁰ mol/l) in a reaction volume of 0.270 ml in theabsence and in the presence of test substances for two hours at 4° C. Toseparate free and receptor-bound calcitriol, a charcoal-dextranabsorption is carried out. 250 μl of a charcoal-dextran suspension isfed to each test tube and incubated at 4° C. for 20 minutes. Then, thesamples are centrifuged at 10,000×g for 5 minutes at 4° C. Thesupernatant is decanted and measured in a β-counter after 1 hour ofequilibration in Picofluor 15™.

The competition curves that are obtained with various concentrations oftest substance as well as of reference substance (unlabeled calcitriol)at constant concentration of the reference substance (³H-calcitriol) areplaced in relation to one another and a competition factor (KF) isdetermined.

It is defined as a quotient of the concentrations of the respective testsubstance and the reference substance, which are necessary for 50%competition:

KF=Concentration of test substance at 50% competition/Concentration ofreference substance at 50% competition

It is common to the compounds according to the invention that they allhave a considerable affinity to the calcitriol receptor.

To determine the acute hypercalcemic action of various calcitriolderivatives, the test that is described below is carried out:

The action of control (solution base), reference substance(1,25(OH)₂-D₃=calcitriol) and test substance is tested in each caseafter one-time subcutaneous administration in groups of 10 healthy malerats (140-170 g). During the testing time, the rats are kept in specialcages to determine the excretion of water and mineral substances. Urineis collected in 2 fractions (0-16 hours and 16-22 hours). An oral doseof calcium (0.1 mmol of calcium in 6.5% alpha-hydroxypropylcellulose, 5ml/animal) replaces at 1600 hours the calcium intake that is lacking byfood deprivation. At the end of the test, the animals are killed bydecapitation and exsanguinated to determine the serum-calcium values.For the primary screen test in vivo, an individual standard dose (200μg/kg) is tested. For selected substances, the result is supported byestablishing a dose-effect relation.

A hypercalcemic action is shown in serum-calcium level values that arehigher than in the control.

The significance of differences between substance groups and controlsand between test substance and reference substance are supported withsuitable statistical processes. The result is indicated as dose ratio DR(DR=factor of test substance dose/reference substance dose forcomparable effects).

The differentiation-stimulating action of calcitriol analogues is alsodetected quantitatively.

It is known in the literature (Mangelsdorf, D. J. et al., J. Cell. Biol.98: 391-398 (1984)), that the treatment of human leukemia cells(promyelocyte cell line HL 60) in vitro with calcitriol induces thedifferentiation of cells to macrophages.

HL 60 cells are cultivated in tissue culture medium (RPMI 10% fetal calfserum) at 37° C. in an atmosphere of 5% CO₂ in air.

For substance testing, the cells are centrifuged off, and 2.0×10⁵cells/ml in phenol red-free tissue culture medium is taken up. The testsubstances are dissolved in ethanol and diluted with tissue culturemedium without phenol red to the desired concentration. The dilutionstages are mixed with the cell suspension at a ratio of 1:10, and 100 μleach of this cell suspension that is mixed with substance is pipettedinto an indentation of a 96-hole plate. For control, a cell suspensionis mixed analogously with the solvent.

After incubation for 96 hours at 37° C. in 5% CO₂ in air, 100 μl of anNBT-TPA solution (nitro blue tetrazolium (NBT), final concentration inthe batch of 1 mg/ml, tetradecanoyl phorbolmyristate-13-acetate (TPA),final concentration in the batch of 2×10⁻⁷ mol/l) is pipetted into eachindentation of the 96-hole plate in the cell suspension.

By incubation for 2 hours at 37° C. and 5% CO₂ in air, NBT is reduced toinsoluble formazan because of the intracellular oxygen radical release,stimulated by TPA, in the cells that are differentiated to macrophages.

To complete the reaction, the indentations of the 96-hole plate aresuctioned off, and the cells are affixed to the bottom of the plate byadding methanol and dried after affixing. To dissolve the intracellularformazan crystals that are formed, 100 μl of potassium hydroxide (2mol/l) and 100 μl of dimethyl sulfoxide are pipetted into eachindentation and ultrasonically treated for 1 minute. The concentrationof formazan is measured by spectrophotometry at 650 nm.

As a yardstick for the differentiation induction of HL 60 cells tomacrophages, the concentration of formed formazan applies. The result isindicated as a dose ratio (DR=factor of test substance dose/referencesubstance dose for comparable semi-maximum effects).

The results of the calcitriol-receptor test and the determination of thedose ratio of the differentiation induction of HL 60 cells and the doseratio for hypercalcemia are summarized below (Tab. 1):

Selected Test Compounds

(5Z,7E,22E)-(1S,3R,24R)-25-Acetyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol7b

(5Z,7E,22E)-(1S,3R,24R)-25-(1-oxobutyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol8b

(5Z,7E,22E)-(1S,3R,24R)-25-benzoyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol10b

(5Z,7E,22E)-(1S,3R,24R)-25-(cyclopropylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol12b

(5Z,7E,22E)-(1S,3R,24R)-25-(2,2-dimethyl-1-oxopropyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol15b

(5Z,7E,22E)-(1S,3R,24R)-25-(1-oxo-2-hexinyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol19b

(5Z,7E,22E)-(1S,3R,24S)-25-acetyl-20-methyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol33a

(5Z,7E,22E)-(1S,3R,24R)-25-acetyl-20-methyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol33b

(5Z,7E,22E)-(1S,3R,24S)-20-methyl-25-(1-oxobutyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol35a

(5Z,7E,22E)-(1S,3R,24R)-20-methyl-25-(1-oxobutyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol35b

(7E,22E)-(1R,3R,24R)-25-acetyl-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol55b

(7E,22E)-(1R,3R,24S)-25-acetyl-20-methyl-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol81a

(7E,22E)-(1R,3R,24R)-25-acetyl-20-methyl-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol81b

Comparison Compound

Calcitriol

TABLE 1 Dose Ratio for Competition Factor Differentiation KF forInduction in HL 60 Compound Receptor Bonding Cells 7b 1 0.5 8b 2 0.9 10b2 6 12b 2 0.2 15b 6 1.1 19b 2 1.5 33a 4 0.5 33b 4 0.4 35a 7 0.3 35b 20.2 55b 4.5 0.2 81a 10 0.2 81b 3 0.1 Calcitriol 1 1

In addition to an affinity to the vitamin D receptor, which iscomparable to that of calcitriol, the compounds listed partially show agreater cell-differentiating activity.

The induction of a hypercalcemia is carried out, however, only at verymuch higher doses than in the case of calcitriol (e.g., dose ratio for7b=300, 8b=100, 15b=300, 19b>300, calcitriol DR=1).

By the reduced property of triggering a hypercalcemia, the substancesaccording to the invention are suitable in a special way for theproduction of pharmaceutical agents for the treatment of diseases thatare characterized by hyperproliferation and deficient celldifferentiation. Included in these are, for example, hyperproliferativediseases of the skin (psoriasis, pityriasis subia pilasis, acne,ichthyosis) as well as tumor diseases and precancerous stages (forexample, tumors of the intestines, carcinomas of the breast, lungtumors, prostate carcinomas, leukemias, T-cell lymphomas, melanomas,Batazell Larzin, squamous carcinoma, actinic keratoses, cervixdysplasias, metastasizing tumors of any type).

Also, for the treatment and prophylaxis of diseases that arecharacterized by a disequilibrium of the immune system, the substancesaccording to the invention are suitable. These include eczemas anddiseases of the atopic Formon series, as well as auto-immune diseases,such as, for example, multiple scleroses, diabetes mellitus type I,myasthenia gravis, lupus erythematosus, scleroderma, bullous skindiseases (pemphigus, pemphigoid), further rejection reactions in thecase of autologous, allogeneic or xenogeneic transplants, as well asAIDS. In all these diseases, the new compounds of general formula I canbe combined advantageously with other substances that have animmunosuppressive action, such as cyclosporin A, FK 506, rapamycin andanti-CD 4 antibodies.

The substances are also suitable for therapy of secondaryhyperparathyroidism and renal osteodystrophia because of the property ofcalcitriols to drop the parathormone synthesis.

Owing to the presence of the vitamin D conceptor in theinsulin-producing cells of the pancreas, the substances are suitable byincreasing the insulin secretion for the therapy of diabetes mellitustype II.

Further, it has been found, surprisingly enough, that by topicalapplication of the compounds according to the invention on the skin ofmice, rats and guinea pigs, an increased reddening of the skin andincrease of the thickness of the epidermis can be induced. The increasein the reddening of the skin is determined from the increase in the redvalue of the skin surface that can be quantified with a calorimeter. Thered value is typically increased 1.5-fold after the substance (dose0.003%) is administered three times at intervals of 24 hours. Theincrease of the thickness of the epidermis is quantified in thehistological preparation. It is typically increased 2.5-fold. The numberof proliferating epidermal cells (cells in the S-phase of the cellcycle) is determined by flow cytometry and is typically increased by afactor of 6.

These properties of the 25-carboxylic acid derivatives in the vitamin Dseries according to the invention can appear suitable for therapeuticuse in the case of atrophic skin, as it occurs in natural skin agingbecause of increased light exposure or medicinally-induced skin atrophyby treatment with glucocorticoids.

Further, it can be assumed that wound healing can be accelerated bytopical application with the new compounds.

In cell populations of the hair follicle, which contribute decisively tohair growth or to hair cycle regulation, it was possible to detectvitamin D₃ receptor proteins (Stumpf, W. E. et al., Cell Tissue Res.238: 489-496; Milde, P. et al., J. Invest., 97: 230-239, 1991). Inaddition, in vitro findings on isolated hair follicle keratinocytes showa proliferation-inhibiting and differentiation-stimulating influence of1,25-(OH)₂-D₃.

From clinical observations, it is known that the vitamin D₃-resistantrickets often accompanies alopecia, which develops in early infancy.Experimental findings show that the vitamin D₃ bonding site of the VDRin this disease mutates, i.e., is defective (Kristjansson, K. et al., J.Clin. Invest. 92: 12-16, 1993). Keratinocytes, which were isolated fromthe hair follicles of these patients, do not react in vitro to theaddition of 1,25-(OH)₂-D₃ (Arase, S. et al., J. Dermatol. Science 2:353-360, 1991).

These findings indicate a decisive role for 1,25 D3 in the regulation ofhair growth.

These analogues are therefore especially suitable for the production ofpharmaceutical agents for the treatment of diseases which accompanydisrupted hair growth (androgenetic alopecia, alopecia areata/totalis,chemotherapy-induced alopecia) or for supporting physiological hairgrowth.

Senile and postmenopausal osteoporosis is characterized by an increasedbone turnover with an overall negative balance. Owing to the boneshrinkage especially of trabecular bones, fractures result to anincreased extent. Owing to the stimulating action of calcitriol, both inthe number and the conduct of synthesis of cells forming new bones(osteoblasts), the substances according to the invention are suitablefor therapy and prophylaxis of senile and postmenopausal osteoporosis(EP 0 634 173 A1), of steroid-induced osteoporosis as well as foraccelerated healing of arthroplasties. For the therapy of various formsof osteoporosis, they can be combined advantageously with estradiol orother derivatives of estrogen.

Finally, it was possible to show that calcitriol increases the synthesisof a growth substance for nerve cells (nerve growth factor) [M. S.Saporito et al. Brain Res. 633, 189-196 (1994)]. The compounds accordingto the invention are therefore also suitable for treating degenerativediseases of the peripheral and central nervous system, such asAlzheimer's disease and amyotrophic lateral sclerosis.

In addition, it has been found that certain compounds of general formulaI in HL 60 cells antagonize, surprisingly enough, the action ofcalcitriol. In the series of 25-alkyl derivatives, the compounds withincreasing chain length on the carbonyl group in the case of constantlygood receptor affinity show considerably weakerdifferentiation-stimulating agonistic activity in HL 60 cells (Tab. 2).

Selected Test Compounds with Antagonistic Action

(5Z,7E,22E)-(1S,3R,24R)-25-(1-Oxopentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol6b

(5Z,7E,22E)-(1S,3R,24R)-25-(1-oxohexyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol9b

[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-(1-oxo-2-hexenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol18b

[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-(3-ethoxy-3-oxo-1-propenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol24b

[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-[3-(1,1-dimethylethoxy)-3-oxo-1-propenyl]-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol26b

(5Z,7E,22E)-(1S,3R,24S)-20-methyl-25-(1-oxooctyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol43a

(5Z,7E,22E)-(1S,3R,24R)-20-methyl-25-(1-oxooctyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol43b

(7E,22E)-(1R,3R,24R)-25-(1-oxopentyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol58b

(7E,22E)-(1R,3R,24R)-25-(1-oxohexyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol61b

(7E,22E)-(1R,3R,24S)-25-(1-oxoheptyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol64a

(7E,22E)-(1R,3R,24R)-20-methyl-25-(1-oxohexyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol61b

Comparison Compound

Calcitriol

TABLE 2 Dose Ratio for Competition Factor Differentiation KF forInduction in HL 60 Compound Receptor Bonding Cells 6b 2 0.5 6b 2 58 9b3 >180 18b 2 330 24b 4 >1000 26b 4 >1000 43a 48 >1000 43b 33 >1000 58b 3160 61b 3 >1000 64a 3.5 120 87b 3 116 Calcitriol 1 1

The compounds 6b, 9b, 18b, 24b, 26b, 43a, 43b, 58b, 61b, 64a and 87bantagonize the action of calcitriol in HL 60 cells. This property iscontinued with increasing chain length in radical Z of general formulaI.

Such compounds that antagonize the action of calcitriol can be used forthe therapy of hypercalcemias, such as, for example, in hypervitaminosisD or intoxication with calcitriol and calcitriol-like active substances,or in the case of increased extrarenal calcitriol synthesis ingranulomatous diseases (sarcoidosis, tuberculosis). Also, paraneoplastichypercalcemias (for example, in osteolytic metastases and tumors withincreased synthesis of parathormone-related peptides) as well as inhypercalcemias in hyperparathyroidism.

In addition, calcitriol antagonists can be used for birth control. Inthe reproductive tracts of female and male animals, the vitamin Dreceptor is expressed. It is known that the female and male fertility ofvitamin-D-deficient animals is reduced. By short-term substitution ofcalcitriol, the reproductive output can be increased. Calcitriolantagonists are therefore able to influence female and male fertility.

Since calcitriol, under certain conditions, shows an immunosuppressiveaction, calcitriol receptor antagonists can also be used asimmunostimulants, e.g., in the case of weak defenses against infections.

Calcitriol is known to be able to modulate hair growth. Calcitriolantagonists can therefore be used therapeutically in the case ofundesirable hair growth, e.g., in hirsutism.

Vitamin D has long been known to play a stimulating role in theformation of arteriosclerotic plaque. In such vascular lesions, acalcitriol-regulated protein, osteopontin, is found to be increased, towhich a role in vascular sclerosis is attributed [R. Eisenstein et al.Arch. Path. 77, 27-35 (1964), L. A. Fitzpatrick et al., J. Clin. Invest.94, 1597-1604 (1994)]. Calcitriol antagonists are therefore suitable fortherapy and prophylaxis of all types of arteriosclerosis.

Finally, calcitriol antagonists are suitable because of the property ofcalcitriol to increase unspecific immune reactions of monocytic cells,for therapy of inflammatory diseases, especially of a chronic nature,such as rheumatoid arthritis, Crohn's disease, ulcerative colitis, andgranulomatous diseases such as sarcoidosis and other foreign-bodyreactions.

This invention thus relates to pharmaceutical preparations that containat least one compound according to general formula I together with apharmaceutically compatible vehicle.

The compounds can be formulated as solutions in pharmaceuticallycompatible solvents or as emulsions, suspensions or dispersions insuitable pharmaceutical solvents or vehicles or as pills, tablets orcapsules, which contain solid vehicles in a way known in the art. Fortopical use, the compounds are advantageously formulated as creams orointments or in a similar form of pharmaceutical agent that is suitablefor topical use. Each such formulation can also contain otherpharmaceutically compatible and nontoxic adjuvants, such as, e.g.,stabilizers, antioxidants, binders, dyes, emulsifiers or flavoringadditives. The compounds are advantageously administered by injection orintravenous infusion of suitable sterile solutions or as oral dosage viathe alimentary tract or topically in the form of creams, ointments,lotions or suitable transdermal patches, as is described in EP-A 0 387077.

The daily dose is approximately 0.1 μg/patient/day—1000 μg (1mg)/patient/day, preferably 1.0 μg/patient/day-500 μg/patient/day.

The production of the vitamin D derivatives of general formula I iscarried out according to the invention from a compound of generalformula II,

in which Y′₁ means a hydrogen atom or a protected hydroxy group and Y′₂means a hydroxy protective group.

The protective groups are preferably alkyl-, aryl- or mixedalkylaryl-substituted silyl groups, e.g., the trimethylsilyl (TMS),triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS),tert-butyldiphenylsilyl (TBDPS) or truisopropylsilyl (TIPS) groups oranother standard hydroxy protective group (see T. W. Greene, P. G. M.Wuts “Protective Groups in Organic Synthesis,” 2^(nd) Edition, JohnWiley & Sons, 1991).

A′ and B′ together can mean a keto group or one of the two substituentscan mean an optionally protected hydroxy group and the other a hydrogenatom (e.g., silyl protective group of the above definition,tetrahydrofuranyl, tetrahydropyranyl, methoxymethyl, methoxyethoxymethylor trimethylsilylethoxymethyl group).

Z′ can have a meaning analogous to Z or optionally exhibit protectivegroup-carrying substituents (e.g., hydroxy protective groups accordingto the above definition).

By simultaneous or successive cleavage of the hydroxy protective groupsand optionally by partial, successive or complete esterification of thefree hydroxy groups, II is converted to a compound of general formula I.

In the case of the silyl protective groups or thetrimethylsilylethoxymethyl group, tetrabutylammonium fluoride,hydrofluoric acid or hydrofluoric acid/pyridine is used for theircleavage; in the case of the other ether groups, the latter are cleavedunder catalytic action of acid, for example, p-toluenesulfonic acid,pyridinium-p-toluenesulfonate, acetic acid, hydrochloric acid,phosphoric acid or an acidic ion exchanger.

The esterification of the free hydroxy groups can be carried outaccording to standard processes with the corresponding carboxylic acidchlorides, bromides or anhydrides.

Separations of diastereomers (e.g., relative to C-24) can be carried outin the final stage or any other preliminary stage.

The production of the starting compounds for general formula II startsfrom various starting compounds depending on the ultimately desiredsubstitution pattern in 10- and 20-position.

For the production of compounds of general formula II, in which R₁ andR₂ together mean an exocyclic methylene group, a start is made fromknown aldehyde III [M. Calverley Tetrahedron 43, 4609 (1987), WO87/00834].

For Y′₁ and Y′₂, the already mentioned definitions apply. Protectivegroups other than those mentioned in the bibliographic references can beobtained by analogous procedure using correspondingly modified silylchlorides (e.g., tert-butyldiphenylsilyl chloride instead oftert-butyldimethylsilyl chloride). By foregoing the corresponding stagesfor 1α-hydroxylation, derivatives of Y′₁═H type can be obtained.

The compounds of general formula III are now converted, analogously toknown processes, into aldehydes of general formula IV (WO 94/07853).

For R3 and R₄, the definitions that are already mentioned above apply.

In building the side chain, both compounds of general formula III andcompounds of general formula IV can now be used. By way of example, thereaction of compounds of general formula III is described below.Analogously to the established sequence (WO 94/07853), carboxylic acidamides of general formula V can thus be generated,

whereby for Y′₁, Y′₂, R₅ and R₆, the already given definitions apply.Preferably, R₅ and R₆ each are to mean a methyl group or both togetherwith carbon atom 25 mean a cyclopropyl ring. R₇ and R₈ meanstraight-chain or branched-chain alkyl groups with 1-9 carbon atoms,whereby especially methyl and ethyl groups are preferred.

Reduction of the keto group with reducing agents, such as, e.g., NaBH₄or NaBH₄/CeCl₃, then results in alcohols of general formula VI.

To establish the natural vitamin D-triene system, a photochemicalisomerization of the compounds of general formula VI is performed.Irradiation with ultraviolet light is carried out in the presence of aso-called triplet sensitizer. Within the scope of this invention,anthracene is used in this respect. By cleavage of the π-bond of the5,6-double bond, rotation of the A ring by 180° around the 5,6-singlebond and reestablishing the 5,6-double bond, the stereoisomerism on the5,6-double bond is reversed, whereby compounds of general formula VIIresult,

whereby Y′₁, Y′₂, R₅, R₆, R₇ and R₈ have the above-mentioned meanings.The diastereomeric alcohols at C-24 can be separated by chromatography.

In building radical Z′, compounds of general formula VII are reacted atlow temperature (−100 to 0° C.) with suitable lithium organyls ofgeneral formula VIII

LiR₉  VIII

The lithium organyls can be generated under standard conditions(halogen-lithium exchange in the case of haloalkanes, metalizations ofaromatic or heteroaromatic systems, metal-lithium exchange, definitionsfor R₉ were already mentioned). In this case, compounds of generalformula II result, whereby for Y′₁, Y′₂, R₅ and R₆, the above-mentionedmeanings apply; R₁ and R2 together mean an exocyclic methylene group; R3and R₄ depending on the selection of aldehyde III or IV have themeanings derived from them; A′ is a hydroxy group and B′ is a hydrogenatom or A′ is a hydrogen atom and B′ is a hydroxy group, and Z′═C(O)—R₉.The hydroxyl group in 24-position (A′ or B′) can be converted before thefinal protective group cleavage optionally with an oxidizing agent suchas, e.g., PCC, PDC, BaMnO₄, MnO₂, Swern conditions, Dess-Martin reagentto a 24-ketone of general formula II, whereby A′ and B′ together form aketo group. The subsequent protective group cleavage must then becarried out, however, under acidic reaction conditions (e.g., acidic ionexchanger, acetic acid, p-toluenesulfonic acid,pyridinium-p-toluenesulfonate), since when using the usual fluoridereagents, conjugated additions of nucleophiles to the enone system areto be feared. A temporary protection of the 24-hydroxy group can becarried out with a protective group as in Y′₁ and Y′₂ to increase insome cases the yield in the addition of lithium-organic compound VIII.

If sterically exacting, branched radicals are to be established for R₉,the reaction of the known ester of general formula IX (WO 94/07853)instead of amide VII is carried out with lithium-organic compound VIII,whereby a compound of general formula II results.

Radical R₁₀ means a straight-chain or branched-chain alkyl group with1-9 carbon atoms.

In principle, the diastereomeric alcohols (relative to C-24) in the caseof the above-mentioned sequences can be reacted separated in advance andreacted separately.

For the synthesis of additional modified derivatives, the compound ofgeneral formula IX is converted by protection of the 24-hydroxy groupinto a compound of general formula X,

whereby R₁₁ means an acid-labile protective group that has a definitionanalogous to Y′₁ or Y′₂ or the tetrahydropyranyl, tetrahydrofuranyl,ethoxyethyl, methoxymethyl or methoxyethoxymethyl group. By reduction ofthe ester unit of general formula X with a reducing agent such as, e.g.,DIBAH, TIBA, LiAlH₄, RedAl, compounds of general formula XI

are obtained.

Under the known reaction conditions, ethers, sulfides and amines can nowbe generated, whereby compounds of general formula II result, for whichZ′═X—R₉, with X═O, S, NH, N-alkyl, N-acyl.

For further structural variation, the compounds of general formula XIcan be reacted to the aldehydes of general formula XII.

This reaction can be carried out with the reagents or methods alreadyindicated for the oxidation of the hydroxy group in 24-position. Inaddition to the already mentioned lithium organyls of general formulaVIII, whose use here results in compounds of general formula II, wherebyZ′═CH(OH)—R₉, perfluorinated alkyl radicals can be introduced hereaccording to methods known in the literature [G. K. Surya Prakash J.Org. Chem. 56, 984 (1991), H. Uno et al. Bull. Chem. Soc. Jpn. 62, 2636(1989)]. By catalytic action of tetrabutylammonium fluoride on thereadily available perfluoroalkyltrimethylsilanes (synthesis from thecommercially available perfluoroalkyl iodides) or by iodine-lithiumexchange of the perfluoroalkyl iodides with methyllithium/lithiumbromide complex, an attack on the carbonyl group can be carried out,whereby after hydrolytic working-up, compounds of general formula XIIIresult,

whereby R₉ can mean straight-chain or branched-chain perfluorinatedalkyl radicals that have 1-9 carbon atoms. The diastereomeric alcoholsare separated by chromatography. The compounds of general formula XIII,on the one hand, can be considered a special case of general formula IIand can be further treated as described there or, on the other hand, canbe converted by oxidation with one of the already previously mentionedoxidizing agents (preferably Swern conditions or Dess-Martin reagent)into a compound of general formula II, whereby Z′═C(O)—R₉.

Aldehyde XII can also be reacted with Wittig, Wittig-Horner orWadsworth-Emmons reagents of type XIV

whereby V=C1-C8 alkyl or alkoxy (straight-chain or branched-chain orcyclic) preferably mean methyl, methoxy, ethyl, ethoxy, butyl, butoxy,phenyl, phenoxy and the definition for R₁₂ was already given above, inthe presence of bases (e.g., NaH, KH, LDA, butyllithium, LiHMDS, NaHMDS,KHMDS), to compounds of general formula XV,

which can be considered a special case of general formula II, for which:

The aldehyde of general formula XII can also be converted by usingmethods known in the literature [L. Van Hijfte Tetrahedron Lett. 30,3655 (1989), S. L. Schreiber J. Am. Chem. Soc. 112, 5583 (1990), J. R.Hauske Tetrahedron Lett. 33, 3715 (1992)] into compounds of generalformula XVI,

which can be considered a special case of general formula II, whereby

The production of compounds of general formula I, if R₁ and R₂ meanhydrogen atoms, is carried out in that a compound of general formulaII′,

whereby the already mentioned meanings exist for Y′₂, R₃, R₄, R₅, R₆,A′, B′ and Z′, is treated analogously to the conditions that aredescribed for the reaction of II.

The production of compounds of general formula II′ is carried out in aconvergent synthesis method, whereby CD and A-ring fragments areseparately structured. For synthesis of the CD fragments, aldehyde XVII,known in the literature [H. H. Inhoffen et al. Chem. Ber. 91, 780(1958), Chem. Ber. 92, 1772 (1959), W. G. Dauben 30, 677 (1989)] isused,

in which P means an acyl-, alkyl- or aryl-substituted silyl ortetrahydropyranyl, tetrahydrofuranyl, methoxymethyl, ethoxyethyl group,an acyl group (e.g., acetyl, benzoyl) or another alcohol protectivegroup (see T. W. Greene, P. G. M. Wuts “Protective Groups in OrganicSynthesis,” 2^(nd) Edition, John Wiley & Sons, Inc., 1991).

According to the known process (WO 94/07853), the modifications at C-20that are already described for the normal series can be introduced,whereby a compound of general formula XVIII results.

For R₃ and R₄, the above-mentioned definitions apply.

For simplification and by way of example, the reaction of the compoundof general formula XVII is described below.

If R₅ and R₆ together with tertiary carbon atom 25 form a cyclopropylring, as known for the normal series (WO 94/07853), by aldol reactionwith an acetoacetic ester component of general formula XIX,

whereby R means a straight-chain alkyl group with 1-6 carbon atoms, acompound of general formula XX can be obtained.

Via intermediate products XXI, XXII and XXIII, the compound of generalformula XXIV is then available.

The chemical manipulations that are necessary in this respect as well asthe meanings of P, R₇, R₈, R₉ and R₁₁ have already been describedelsewhere. By reduction of the keto group with a reducing agent (e.g.,NaBH₄, NaBH₄/CeCl₃, LiAlH₄, DIBAH, TIBA, RedAl), a compound of generalformula XXV is available, whose hydroxy group is provided with anacid-stable protective group that is to be removed by basic action(e.g., R₁₄=acetyl, propionyl, pivaloyl, benzoyl group), whereby acompound of general formula XXVI is obtained. Separations ofdiastereomeric hydroxy groups are carried out in each case in suitableintermediate stages.

In the selection of suitable protective groups (e.g., P═Et₃Si, R₁₁═THP,R₁₄═Ac), group P can be selectively cleaved and by oxidation of thehydroxy group, the compound of general formula XXVII can be convertedwith an oxidizing agent (PCC, PDC, BaMnO₄, Swern conditions, Dess-Martinreagent) into a CD fragment of general formula XXVIII.

The compounds of general formula XXVIII are now converted by reactionwith the anion of the phosphine oxide of general formula XXIX, known inthe literature, that is produced by a base such as n-butyllithium or LDA[H. F. DeLuca et al. Tetrahedron Lett. 32, 7663, (1991)],

in which Y′₂ has the already described meaning, into the correspondingcompounds of general formula XXX.

Successively or simultaneously, the protective groups are now removed(R₁₄ by basic hydrolysis, R₁₁ as well as Y′₂ by acid hydrolysis orfluoride reagents) and, as desired, one or both of the side chainhydroxy groups are oxidized with the already frequently mentionedoxidizing agent, whereby compounds of general formula I result, forwhich: R₁ and R₂ are hydrogen atoms and R₅ and R₆ together with tertiarycarbon atom 25 form a cyclopropyl ring. The additional definitions werealready mentioned.

As an alternative, protective group P in general formula XXIII can beselectively cleaved, if: P=silyl protective group, R₁₁=tetrahydropyranylor tetrahydrofuranyl protective group. This can be carried out, e.g.,with tetrabutylammonium fluoride, whereby compounds of general formulaXXXI result.

The free hydroxy group can now be oxidized with an oxidizing agent (PCC,PDC, BaMnO₄, Swern conditions, Dess-Martin reagent), whereby compoundsof general formula XXXII are produced,

which are converted with the anion of phosphine oxide XXIX that isproduced by a base (n-butyllithium, lithium diisopropylamide) intocompounds of general formula XXXIII.

Analogously to the compounds in the normal series (e.g., VII), thebuilding of radical Z′ now takes place, whereby compounds of generalformula XXXIV result.

These can be considered a special case of general formula II′, wherebyall variables have already been described previously. The furthertreatment of the compounds of general formula II′ has also beenindicated above.

If R₅ and R₆ do not form a cyclopropyl ring together with tertiarycarbon atom 25, rather the other above-mentioned definitions are toapply, the building of the side chain takes place with a somewhatmodified synthesis method. The known CD-portion of general formula XXXV(WO 94/07853) can be converted, analogously to the normal series, intoderivatives of general formulas XXXVI and XXXVII,

whereby all variables have the already mentioned definitions. Thediastereomers can be separated into suitable intermediate stages.

By direct reaction of the lithium organyls of general formula VIII(LiR₉) with compounds of general formulas XXXVI and XXXVII, compounds ofgeneral formula XXXVIII can now be generated, and as shown before, areconverted into a compound of general formula II′.

The diastereomeric alcohols (relative to C-24) can be reacted separatedin advance and reacted separately.

In principle, the introduction of correspondingly substituted sidechains or their precursors can also be carried out on aldehydes ofgeneral formulas III or IV or their 5Z-isomers with use of establishedsynthesis methods.

The following examples are used for a more detailed explanation of theinvention.

BRIEF DESCRIPTION OF DRAWINGS

FIGS. 1-14 are reaction schemes depicting the syntheses of C-25substituted vitamin D derivatives.

EXAMPLE 1(5Z,7E,22E)-(1S,3R,24R)-25-(1-Oxopentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(6b)

a) An amount of 5.0 g of(5E,7E,22E)-(1S,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-24-oxo-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-25-carboxylicacid 1 (WO 94/07853) and 1.01 g of N-hydroxysuccinimide are dissolved in21 ml of methylene chloride and mixed with 1.87 g ofN,N′-dicyclohexylcarbodiimide at 0° C. After 1.5 hours, 2.04 ml of a 40%aqueous dimethylamine solution is added and stirred for another 30minutes at 0° C. After 3 hours at room temperature, the reaction mixtureis chromatographed on silica gel with ethyl acetate/hexane (1:4). 2.08 gof(5E,7E,22E)-(1S,3R)-1,3-bis-[[dimethyl(1,1-dimethyl-ethyl)silyl]oxy]-N,N-dimethyl-24-oxo-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-25-carboxylicacid amide 2 is obtained as a colorless compound.

b) 1.39 g of amide 2 is dissolved in 3.3 ml of THF and 7.7 ml ofmethanol and mixed with 7.7 ml of a 0.4 molar methanolic ceriumtrichloride (hydrate) solution. 210 mg of sodium borohydride is nowadded in portions at 0° C. It is stirred for 45 more minutes at 0° C.and then mixed with an ice/water mixture. Then, it is extracted withethyl acetate, dried on sodium sulfate and concentrated by evaporation.The oily residue (1.32 g) is a diastereomer mixture that consists of(5E,7E,22E)-(1S,3R,24S)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-N,N-dimethyl-24-hydroxy-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-25-carboxylicacid amide 3a and the 24R-diastereomer 3b.

c) 2.48 g of the epimer mixture 3a and 3b is dissolved in 348 ml oftoluene and, after 383 mg of anthracene and 7 drops of triethylamine areadded, it is irradiated through Pyrex glass with a mercury high-pressurelamp (Heraeus TQ 150) for 19 minutes under nitrogen. The reactionmixture that is concentrated by evaporation is mixed with hexane,filtered and again concentrated by evaporation. The residue of 2.82 g isa mixture of(5Z,7E,22E)-(1S,3R,24S)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-N,N-dimethyl-24-hydroxy-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-25-carboxylicacid amide 4a and the corresponding 24R-diastereomer 4b.

d) The diastereomer mixture that consists of 4a and 4b (2.82 g) isdissolved in 28 ml of THF and mixed drop by drop with 6.53 ml ofn-butyllithium solution (1.6 M in hexane) at 0° C. After 75 minutes,saturated ammonium chloride solution is added to the reaction solution,extracted with ethyl acetate, dried on sodium sulfate and concentratedby evaporation. By chromatography of the residue on silica gel withethyl acetate/hexane, 0.84 g of(5Z,7E,22E)-(1S,3R,24S)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-(1-oxopentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen-24-ol5a and 0.64 g of(5Z,7E,22E)-(1S,3R,24R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-(1-oxopentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen-24-ol5b are obtained in the elution sequence as oils.

e) 0.62 g of epimer 5b is allowed to stand in 24.9 ml of THF with 1.32 gof tetrabutylammonium fluoride (trihydrate) overnight at roomtemperature. The reaction mixture is then poured onto a mixture ofice/sodium bicarbonate solution/sodium chloride solution. Afterextraction with ethyl acetate, the organic phase is dried on sodiumsulfate and concentrated by evaporation. Chromatography of the residueon silica gel with ethyl acetate/hexane yields 125 mg of title compound6b as a foam.

¹H-NMR (300 MHz, CDCl₃): δ=0.57 ppm (s, 3H); 0.91 (t, 3H); 1.00 (m, 2H);1.05 (d, 3H); 1.22 (m, 2H); 2.15 (t, 2H); 3.29 (brd, 1H); 4.08 (m,1H);4.22 (m, 1H); 4.42 (m, 1H); 5.00 (brs, 1H); 5.32 (brs, 1H); 5.35 (dd,1H); 5.49 (dd, 1H); 6.01 (d, 1H); 6.38 (d, 1H)

EXAMPLE 2(5Z,7E,22E)-(1S,3R,24S)-25-(1-Oxopentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(6a)

Analogously to the implementation according to 1e), epimer 5a isreacted, whereby title compound 6a is obtained as a crystallizing oil.

¹H-NMR (300 MHz, CDCl₃): δ=0.57 ppm (s, 3H); 0.90 (t, 3H); 1.00 (m, 2H);1.05 (d, 3H); 1.22 (m, 2H); 2.16 (t, 2H); 3.25 (brs, 1H); 4.12 (m 1H);4.23 (m, 1H); 4.43 (m, 1H); 5.00 (brs, 1H); 5.32 (brs, 1H); 5.36 (dd,1H); 5.55 (dd, 1H); 6.01 (d, 1H); 6.38 (d, 1H)

EXAMPLE 3(5Z,7E,22E)-(1S,3R,24R)-25-Acetyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(7b)

Starting with the epimer mixture 4a and 4b, title compound 7b isobtained, analogously to Example 1d)-e) as crystals with methyllithium(melting point: 138-140° C.).

¹H-NMR (300 MHz, CDCl₃): δ=0.57 ppm (s, 3H); 1.00 (m, 2H); 1.05 (d, 3H);1.22 (m, 2H); 1.96 (s, 3H); 3.16 (brd, 1H); 4.12 (m, 1H); 4.23 (m, 1H);4.43 (m, 1H); 5.00 (brs, 1H); 5.32 (brs, 1H); 5.36 (dd, 1H); 5.50 (dd,1H); 6.01 (d, 1H); 6.38 (d, 1H)

EXAMPLE 4(5Z,7E,22E)-(1S,3R,24R)-25-(1-Oxobutyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(8b)

Starting with the epimer mixture 4a and 4b, title compound 8b isobtained, analogously to Example 1d)-e), as a foam with propyllithium(that consists of n-propyl bromide and lithium in ether).

¹H-NMR (300 MHz, CDCl₃): δ=0.57 ppm (s, 3H); 0.90 (t, 3H); 1.00 (m, 2H);1.05 (d, 3H); 1.20 (m, 2H); 2.13 (t, 2H); 3.25 (brs, 1H); 4.10 (m, 1H);4.23 (m, 1H); 4.43 (m, 1H); 5.00 (brs, 1H); 5.32 (brs, 1H); 5.38 (dd,1H); 5.50 (dd, 1H); 6.01 (d, 1H); 6.38 (d, 1H)

EXAMPLE 5(5Z,7E,22E)-(1S,3R,24R)-25-(1-Oxohexyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(9b)

Starting with the epimer mixture 4a and 4b, title compound 9b isobtained, analogously to Example 1d)-e), as a foam with pentyllithium(that consists of n-pentyl bromide and lithium in ether).

¹H-NMR (300 MHz, CDCl₃): δ=0.57 ppm (s, 3H); 0.90 (t, 3H); 1.00 (m, 2H);1.05 (d, 3H); 1.22 (m, 2H); 2.13 (t, 2H); 3.30 (brs, 1H); 4.08 (m, 1H);4.23 (m, 1H); 4.43 (m, 1H); 5.00 (brs, 1H); 5.32 (brs, 1H); 5.37 (dd,1H); 5.50 (dd, 1H); 6.01 (d, 1H); 6.38 (d, 1H)

EXAMPLE 6 (10b)(5Z,7E,22E)-(1S,3R,24R)-25-Benzoyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol

Starting with the epimer mixture 4a and 4b, title compound 10b isobtained, analogously to Example 1d)-e), as a foam with phenyllithium.

¹H-NMR (300 MHz, CDCl₃): δ=0.57 ppm (s, 3H); 1.01 (d, 3H); 1.08 (m, 2H);1.22 (m, 2H); 2.20 (brd, 1H); 4.23 (m, 1H); 4.45 (m, 2H); 5.00 (brs,1H); 5.31 (dd, 1H); 5.32 (dd, 1H); 5.48 (dd, 1H); 6.01 (d, 1H); 6.38 (d,1H); 7.45 (m, 3H); 7.75 (d, 2H)

EXAMPLE 7(5Z,7E,22E)-(1S,3R,24R)-25-(2-Furanylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(11b)

Starting with the epimer mixture 4a and 4b, title compound 11b isobtained, analogously to Example 1d)-e), as a solid with 2-furyllithium(production of furan with n-butyllithium in THF) in the case of inverseaddition (−78° C., then 0° C., 1 hour).

¹H-NMR (300 MHz, CDCl₃): δ=0.57 ppm (s, 3H); 1.02 (d, 3H); 1.08 (m, 2H);1.18 (m, 2H); 3.12 (brd, 1H); 4.22 (m, 2H); 4.42 (m, 1H); 5.00 (brs,1H); 5.32 (dd, 1H); 5.43 (dd, 1H); 5.53 (dd, 1H); 6.01 (d, 1H); 6.38 (d,1H); 6.50 (m, 1H); 7.20 (d, 1H); 7.51 (brs, 1H)

EXAMPLE 8(5Z,7E,22E)-(1S,3R,24R)-25-(Cyclopropylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(12b)

Starting with the epimer mixture 4a and 4b, the title compound isobtained, analogously to Example 1d)-e), as a foam with cyclopropyllithium (that consists of cyclopropyl bromide and lithium in ether).

¹H-NMR (300 MHz, CDCl₃): δ=0.57 ppm (s, 3H); 0.83 (m, 2H); 1.05 (m,10H); 3.48 (brd, 1H); 4.13 (m, 1H); 4.23 (m, 1H); 4.45 (m, 1H); 5.00(brs, 1H); 5.32 (dd, 1H); 5.40 (dd, 1H); 5.50 (dd, 1H); 6.01 (d, 1H);6.38 (d, 1H) cl EXAMPLE 9

(5Z,7E,22E)-(1S,3R,24R)-25-(2,2-Dimethyl-1-oxopropyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(15b)

a) 580 mg of(5Z,7E,22E)-(1S,3R,24R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-24-hydroxy-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-25-carboxylicacid ethyl ester 13b (WO 94/07853) in 6.4 ml of diethyl ether is mixeddrop by drop with 2.04 ml of tert-butyllithium (1.7 M in pentane) at−78° C. After 1 hour at −78° C., ammonium chloride solution is added,extracted with ethyl acetate, the organic phase is washed with sodiumchloride solution, dried on sodium sulfate and concentrated byevaporation. Chromatography of the oily residue on silica gel with ethylacetate/hexane yields 220 mg of(5Z,7E,22E)-(1S,3R,24R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-(2,2-dimethyl-1-oxopropyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen-24-ol14b as an oil.

b) 220 mg of 14b is dissolved in 8.8 ml of THF and allowed to stand with467 mg of tetrabutylammonium fluoride (trihydrate) overnight at roomtemperature. Working-up and isolation are carried out analogously toExample 1e), whereby title compound 15b accumulates as a solid.

¹H-NMR (300 MHz, CDCl₃): δ=0.57 ppm (s, 3H); 0.80-1.00 (m, 4H); 1.05 (d,3H); 1.20 (s, 9H); 3.00 (brs, 1H); 4.09 (m, 1H); 4.23 (m, 1H); 4.43 (m,1H); 5.00 (brs, 1H); 5.29 (dd, 1H); 5.32 (brs, 1H); 5.52 (dd, 1H); 6.01(d, 1H); 6.38 (d, 1H)

EXAMPLE 10(5Z,7E,22E)-(1S,3R,24R)-25-(1-Oxoheptyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(16b)

Starting with the epimer mixture 4a and 4b, title compound 16b isobtained, analogously to Example 1d)-e), as a colorless foam withhexyllithium (that consists of 1-hexyl bromide and lithium in ether).

¹H-NMR (300 MHz, CDCl₃): δ=0.57 ppm (s, 3H); 0.90 (m, 5H); 1.05 (d, 3H);2.13 (t, 2H); 3.30 (brd, 1H); 4.08 (m, 1H); 4.23 (m, 1H); 4.43 (m, 1H);5.00 (brs, 1H); 5.32 (brs, 1H); 5.37 (dd, 1H); 5.50 (dd, 1H); 6.01 (d,1H); 6.38 (d, 1H)

EXAMPLE 11(5Z,7E,22E)-(1S,3R,24R)-25-(2-Pyridinylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(17b)

2.03 ml of 2-bromopyridine in 38 ml of diethyl ether is mixed drop bydrop with 13.3 ml of n-butyllithium (1.6 M in hexane) at −78° C. After30 minutes, 1.98 g of(5Z,7E,22E)-(1S,3R,24R)-1,3-bis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-24-hydroxy-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-25-carboxylicacid ethyl ester 13b (WO 94/07853) in 19 ml of diethyl ether is added indrops. After 1.5 hours at −78° C., the reaction solution is mixed withsaturated ammonium chloride solution, then extracted with ethyl acetate,the organic phase is dried on sodium sulfate and concentrated byevaporation. By chromatography on silica gel with ethyl acetate/hexane,1.52 g of a colorless oil is obtained, which is dissolved in 60.2 ml ofTHF and allowed to stand with 3.19 g of tetrabutylammonium fluoride(trihydrate) overnight at room temperature. Working-up and isolation arecarried out analogously to Example 1e). After recrystallization fromisopropanol/water, the title compound with a melting point of 120-121°C. is obtained.

EXAMPLE 12[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-(1-Oxo-2-hexenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(18b)

11.5 ml of n-butyllithium (1.6 M in hexane) is added in drops at 0° C.to 3.61 g of (E)-1-iodo-1-pentene [that consists of 1-pentine, DIBAH andiodine analogously to J. K. Stille et al. J. Am. Chem. Soc. 109, 2138(1987), T. Yokoo Synlett 645 (1994)] in 90 ml of hexane. After 15minutes, 180 mg of(5Z,7E,22E)-(1S,3R,24R)-N,N-dimethyl-1,3,24-trihydroxy-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-25-carboxylicacid amide [obtained from the epimer mixture 4a and 4b (Example 1c) bychromatography on silica gel and treatment with tetrabutylammoniumfluoride (trihydrate)] in 18 ml of THF is added in drops. After 3 hoursat 0° C. in ice-cold ammonium chloride solution, the reaction mixture isstirred in. After extraction with ethyl acetate, drying of the organicphase on sodium sulfate and chromatography on silica gel with ethylacetate/hexane, the title compound is obtained as a colorless foam.

¹H-NMR (300 MHz, CDCl₃): δ=0.57 ppm (s, 3H); 0.90 (t, 3H); 1.05 (d, 5H);3.45 (brs, 1H); 4.11 (m, 1H); 4.23 (m, 1H); 4.43 (m, 1H); 5.00 (brs,1H); 5.35 (brs, 1H); 5.40 (dd, 1H); 5.56 (dd, 1H); 5.91 (d, 1H); 6.01(d, 1H); 6.38 (d, 1H); 6.98 (dt, 1H)

EXAMPLE 13(5Z,7E,22E)-(1S,3R,24R)-25-(1-Oxo-2-hexinyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(19b)

5.75 ml of n-butyllithium (1.6 M in hexane) is added in drops to 0.9 mlof 1-pentine in 45 ml of hexane at −5° C. After 1 hour at −5° C., 90 mgof(5Z,7E,22E)-(1S,3R,24R)-N,N-dimethyl-1,3,24-trihydroxy-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-25-carboxylicacid amide in 9 ml of THF is added in drops. After 3 hours at 0° C., thereaction mixture is stirred into saturated ammonium chloride solution.After extraction with ethyl acetate, drying of the organic phase onsodium sulfate and chromatography on silica gel with ethylacetate/hexane, the title compound is obtained as a colorless solid.

¹H-NMR (300 MHz, CDCl₃): δ=0.57 ppm (s, 3H); 1.00 (m, 6H); 1.10 (m, 2H);1.45 (m, 2H); 2.32 (t, 4H); 3.12 (brd, 1H); 4.23 (m, 2H); 4.43 (m, 1H);5.00 (brs, 1H); 5.32 (brs, 1H); 5.37 (dd, 1H); 5.51 (dd, 1H); 6.01 (d,1H); 6.38 (d, 1H)

EXAMPLE 14[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-(3-Ethoxy-3-oxo-1-propenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(24b)

a) 2.02 g of(5Z,7E,22E)-(1S,3R,24R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-24-hydroxy-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-25-carboxylicacid ethyl ester 13b (WO 94/07853) is dissolved in 20 ml of DMF andmixed with 761 mg of imidazole as well as 843 mg of t-butyldimethylsilylchloride. It is stirred overnight at room temperature and worked up inaqueous form (addition of sodium chloride solution, ethyl acetateextraction, washing of the organic phase with sodium chloride solution,drying on sodium sulfate, concentration by evaporation). Bychromatography on silica gel with ethyl acetate/hexane, 2.12 g of(5Z,7E,22E)-(1S,3R,24R)-1,3,24-tris[[dimethyl(1,1-dimethlethyl)silyl]oxy]-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-25-carboxylicacid ethyl ester 20b is obtained as a colorless foam.

¹H-NMR (300 MHz, CDCl₃): δ=0.05 ppm (s, 18H); 0.52 (s, 3H); 0.87 (s,27H); 1.01 (d, 3H); 1.22 (t, 3H); 4.08 (q, 2H); 4.18 (m, 1H); 4.37 (m,1H); 4.68 (d, 1H); 4.85 (brs, 1H); 5.08 (brs, 1H); 5.22 (dd, 1H); 5.43(dd, 1H); 6.00 (d, 1H); 6.22 (d, 1H)

b) 2.10 g of trisilyl ether 20b is dissolved in 15 ml of THF, and 12 mlof DIBAH solution (1 M in toluene) is added in drops at 0° C. It isstirred for 1 more hour at 0° C., and then 4 ml of water is added. Theprecipitate is removed by filtration, rewashed with ethyl acetate, theorganic phase is washed with water, dried on sodium sulfate andconcentrated by evaporation. Chromatography on silica gel with ethylacetate/hexane yields 1.53 g of(5Z,7E,22E)-(1S,3R,24R)-1,3,24-tris[[dimethyl(1,1-dimethylethyl)silyl]oxy]-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-25-methanol21b as a colorless foam.

¹H-NMR (300 MHz, CDCl₃): δ=0.06 ppm (s, 18H); 0.54 (s, 3H); 0.90 (s,27H); 1.05 (d, 3H); 3.05 (m, 2H); 3.61 (d, 1H); 4.00 (d, 1H); 4.19 (m,1H); 4.38 (m, 1H); 4.86 (brs, 1H); 5.08 (brs, 1H); 5.74 (m, 2H); 6.01(d, 1H); 6.22 (d, 1H)

c) 1.5 g of alcohol 21b is dissolved in 50 ml of methylene chloride andmixed in portions with a total of 1.2 g of pyridinium chlorochromate atroom temperature. It is stirred for 3 more hours at room temperature,diluted with ether, filtered, concentrated by evaporation and theresidue is chromatographed on silica gel with ethyl acetate/hexane,whereby 570 mg of(5Z,7E,22E)-(1S,3R,24R)-1,3,24-tris[[dimethyl(1,1-dimethylethyl)silyl]oxy]-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-25-carbaldehyde22b is obtained as a colorless foam.

¹H-NMR (300 MHz, CDCl₃): δ=0.05 ppm (s, 18H); 0.55 (s, 3H); 0.90 (s,27H); 1.05 (d, 3H); 4.19 (m, 1H); 4.38 (m, 1H); 4.45 (d, 1H); 4.87 (brs,1H); 5.08 (brs, 1H); 5.32 (dd, 1H); 5.53 (dd, 1H); 6.01 (d, 1H); 6.23(d, 1H); 9.29 (s, 1H)

d) 34 mg of sodium hydride (65%) in 5 ml of THF is introduced, and 216mg of diethylphosphonoacetic acid ethyl ester is added. Then, 100 mg ofaldehyde 22b in 5 ml of THF is added in drops and heated for 1 hour to50° C. After cooling, it is worked up in aqueous form analogously to14a) and chromatographed on silica gel with ethyl acetate/hexane,whereby 100 mg of[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-(3-ethoxy-3-oxo-1-propenyl)-1,3,24-tris[[dimethyl(1,1-dimethylethyl)silyl]oxy]-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene23b is obtained as a colorless foam.

¹H-NMR (300 MHz, CDCl₃): δ=0.06 ppm (s, 18H); 0.53 (s, 3H); 0.89 (s,27H); 1.02 (d, 3H); 1.25 (t, 3H); 3.89 (d, 1H); 4.16 (q, 2H); 4.18 (m,1H); 4.38 (m, 1H); 4.85 (brs, 1H); 5.18 (brs, 1H); 5.30 (dd, 1H); 5.41(dd, 1H); 5.68 (d, 1H); 6.00 (d, 1H); 6.22 (d, 1H); 6.98 (d, 1H)

e) 100 mg of ester 23b is dissolved in 10 ml of THF, 287 mg oftetrabutylammonium fluoride (trihydrate) is added and stirred overnightat room temperature. Analogously to 14a), it is worked up in aqueousform and chromatographed on silica gel with ethyl acetate/hexane,whereby 39 mg of title compound 24b accumulates as a colorless foam.

¹H-NMR (300 MHz, CDCl₃): δ=0.53 ppm (s, 3H); 1.05 (d, 3H); 1.27 (t, 3H);3.91 (d, 1H); 4.15 (q, 2H); 4.20 (m, 1H); 4.41 (m, 1H); 4.97 (brs, 1H);5.30 (brs, 1H); 5.40 (dd, 1H); 5.58 (dd, 1H); 5.79 (d, 1H); 5.99 (d,1H); 6.37 (d, 1H); 6.93 (d, 1H)

EXAMPLE 15[5Z,7E,22E,25(E)]-(1S,3R,24S)-25-(3-Ethoxy-3-oxo-1-propenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(24a)

3.1 g of(5Z,7E,22E)-(1S,3R,24S)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-24-hydroxy-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-25-carboxylicacid ethyl ester 13a (WO 94/07853) is reacted to title compound 24aanalogously to 14a), b), c), d) and e), which accumulates as a colorlessfoam.

¹H-NMR (300 MHz, CDCl₃): δ=0.56 ppm (s, 3H); 1.02 (d, 3H); 1.28 (t, 3H);3.93 (d, 1H); 4.16 (q, 2H); 4.21 (m, 1H); 4.41 (m, 1H); 4.99 (brs, 1H);5.31 (brs, 1H); 5.41 (dd, 1H); 5.61 (dd, 1H); 5.80 (d, 1H); 6.00 (d,1H); 6.38 (d, 1H); 6.93 (d, 1H)

EXAMPLE 16[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-[3-(1,1-Dimethylethoxy)-3-oxo-1-propenyl]-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(26b)

a) Analogously to 14d), aldehyde 22b is reacted withdiethylphosphonoacetic acid-t-butyl ester, whereby[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-[3-(1,1-dimethylethoxy)-3-oxo-1-propenyl]-1,3,24-tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene25b accumulates as a colorless foam.

¹H-NMR (300 MHz, CDCl₃): δ=0.06 ppm (s, 18H); 0.53 (s, 3H); 0.89 (s,27H); 1.02 (d, 3H); 1.46 (s, 9H); 3.91 (d, 1H); 4.18 (m, 1H); 4.37 (m,1H); 4.87 (brs, 1H); 5.18 (brs, 1H); 5.29 (dd, 1H); 5.41 (dd, 1H); 5.59(d, 1H); 6.00 (d, 1H); 6.22 (d, 1H); 6.81 (d, 1H)

b) Analogously to 14e), title compound 26b is obtained as a colorlessfoam.

¹H-NMR (300 MHz, CDCl₃): δ=0.58 ppm (s, 3H); 1.06 (d, 3H); 1.47 (s, 9H);3.39 (dd, 1H); 4.22 (m, 1H); 4.42 (m, 1H); 5.00 (brs, 1H); 5.23 (dd,1H); 5.31 (sbr, 1H); 5.52 (dd, 1H); 5.68 (d, 1H); 6.01 (d, 1H); 6.38 (d,1H); 6.79 (d, 1H)

EXAMPLE 17(5Z,7E,22E)-[1S,3R,24S,25(S)]-25-(1-Hydroxy-2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoroheptyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(27aα) and(5Z,7E,22E)-[1S,3R,24S,25(R)]-25-(1-hydroxy-2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoroheptyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(27aβ)

60 mg of aldehyde 22a [synthesis analogous to 22b from 13a instead of13b, see 14a)-c)] with 107 mg of perfluorohexyl iodide in diethyl etheris introduced at −78° C., and 0.12 ml of methyllithium/lithium bromidecomplex (1.6 M in ether) is added in drops. After 30 minutes at −78° C.,it is worked up in aqueous form analogously to 14a), and the residue ispurified by chromatography on silica gel with ethyl acetate/hexane. Theproduct that accumulates (22 mg) is dissolved in 10 ml of THF, mixedwith 60 mg of tetrabutylammonium fluoride (trihydrate) and stirredovernight at room temperature. After renewed aqueous working-up, thediastereomeric alcohols are now separated by preparative thin-layerchromatography with ethyl acetate/hexane as mobile solvent, whereby 0.9mg of title compound 27aα and 2.45 mg of title compound 27aβ accumulateas colorless foams.

¹H-NMR (300 MHz, CD₂Cl₂):

27aα δ=0.54 ppm (s, 3H); 1.00 (d, 3H); 3.35 (dd, 1H); 4.15 (m, 2H); 4.35(m, 1H); 4.75 (brs, 1H); 4.93 (brs, 1H); 4.97 (d, 1H); 5.08 (dd, 1H);5.27 (dd, 1H); 5.53 (dd, 1H); 6.00 (d, 1H); 6.34 (d, 1H)

27aβ δ=0.55 ppm (s, 3H); 1.02 (d, 3H); 3.36 (d, 1H); 3.76 (d, 1H); 4.07(dd, 1H); 4.16 (m, 1H); 4.36 (m, 1H); 4.95 (brs, 1H); 5.18 (brs, 1H);5.51 (dd, 1H); 5.62 (dd, 1H); 6.00 (d, 1H); 6.35 (d, 1H)

EXAMPLE 18(5Z,7E,22E)-[1S,3R,24R,25(S)]-25-(1-Hydroxy-2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoroheptyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(27bα) and(5Z,7E,22E)-[1S,3R,24R,25(R)]-25-(1-hydroxy-2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoroheptyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(27bβ)

Analogously to 17), 50 mg of aldehyde 22b is reacted, whereby ultimately4.50 mg of title compound 27bα and 3.15 mg of title compound 27bβaccumlate as colorless foams.

¹H-NMR (300 MHz, CD₂Cl₂):

27bα δ=0.54 ppm (s, 3H); 1.02 (d, 3H); 3.33 (dd, 1H); 4.15 (m, 1H); 4.16(m, 1H); 4.36 (m, 1H); 4.84 (brs, 1H); 4.95 (brs, 1H); 4.99 (d, 1H);5.07 (dd, 1H); 5.17 (dd, 1H); 5.51 (dd, 1H); 6.00 (d, 1H); 6.35 (d, 1H)

27bβ δ=0.55 ppm (s, 3H); 1.03 (d, 3H); 3.52 (d, 1H); 3.73 (dd, 1H); 3.98(s, 1H); 4.17 (m, 2H); 4.36 (m, 1H); 4.95 (brs, 1H); 5.18 (brs, 1H);5.56 (m, 2H); 6.00 (d, 1H); 6.35 (d, 1H)

EXAMPLE 19(5Z,7E,22E)-(1S,3R,24R)-25-Acetyl-20-methyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(33b) and(5Z,7E,22E)-(1S,3R,24S)-25-acetyl-20-methyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(33a)

a) Lithium diisopropylamide (LDA) is prepared from 3.4 ml ofdiisopropylamine and 8.7 ml of n-butyllithium solution (2.5 M in hexane)in 250 ml of THF at 0° C. under argon, and the solution is then cooledto −78° C. 3.5 g of 1-acetylcyclopropanecarboxylic acid methyl ester [D.F. Taber et al. J. Org. Chem. 57, 456 (1992)] is now added in drops andstirred for 1 hour. Then, 3.2 g of(5Z,7E)-(1S,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-20-methyl-9,10-secopregna-5,7,10(19)-triene-20-carbaldehyde(WO 93/12081) 28 in 20 ml of THF is added in drops and stirred for 2hours at 0° C. After saturated ammonium chloride solution is added at−20° C., it is diluted with saturated sodium chloride solution,extracted with ethyl acetate with the addition of 5% oxalic acid, driedon sodium sulfate and concentrated by evaporation. The thus obtainedcrude product(5Z,7E,22E)-(1S,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-20-methyl-24-oxo-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-25-carboxylicacid 29 (4.3 g of a solid compound) is further reacted withoutadditional purification.

b) An amount of 2.23 g of 29, 990 mg of dicyclohexylcarbodiimide and 552mg of N-hydroxysuccinimide are dissolved in 30 ml of methylene chlorideand stirred for 2 hours under argon. 0.81 ml of dimethylamine is nowadded, and the mixture is stirred overnight at room temperature. It isdiluted with sodium chloride solution, extracted with methylenechloride, dried on sodium sulfate, the solvent is removed, and theresidue is purified by chromatography on silica gel with ethylacetate/hexane, whereby 1.5 g of(5Z,7E,22E)-(1S,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-24-oxo-N,N,20-trimethyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-25-carboxylicacid amide 30 accumulates as a colorless foam.

¹H-NMR (300 MHz, CDCl₃): δ=0.07 ppm (s, 12H); 0.48 (s, 3H); 0.86 (s,18H); 1.07 (s, 3H); 1.10 (s, 3H); 2.91 (s, 3H); 2.98 (s, 3H); 4.18 (m,1H); 4.37 (m, 1H); 4.82 (brs, 1H); 5.18 (brs, 1H); 5.97 (d, 1H); 6.13(d, 1H); 6.19 (d, 1H); 7.20 (d, 1H)

c) 3.2 g of 30 is reacted analogously to 1b), and, after chromatographyon silica gel with ethyl acetate/hexane, 2.7 g of(5Z,7E,22E)-(1S,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-24-hydroxy-N,N,20-trimethyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-25-carboxylicacid dimethylamide 31 is obtained as a diastereomer mixture relative toC-24 as a colorless foam.

¹H-NMR (300 MHz, CDCl₃): δ=0.07 ppm (s, 12H); 0.55 (s, 3H); 0.89 (s,18H); 1.02/1.03 (2×s, 3H); 1.08/1.09 (2×s, 3H); 3.04 (brs, 6H); 4.02 (m,1H); 4.19 (m, 1H); 4.39 (m, 1H); 4.87 (brs, 1H); 5.20 (brs, 1H); 5.27(d, 1H); 5.88 (d, 1H); 6.00 (d, 1H); 6.22 (d, 1H)

d) 300 mg of 31 in 2 ml of diethyl ether is introduced, and 1.03 ml ofmethyllithium solution (1.3 M in diethyl ether) is added in drops at−78° C. under argon. It is stirred for 30 minutes at −78° C. and foranother 30 minutes at −30° C. Then, it is quenched with sodium chloridesolution, extracted with ethyl acetate, the combined organic phases arewashed with sodium chloride solution, dried on sodium sulfate, and thesolvent is removed. Chromatography of the crude product on silica gelwith ethyl acetate/hexane yields 165 mg of(5Z,7E,22E)-(1S,3R)-25-acetyl-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-20-methyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen-24-ol32 as a colorless foam.

¹H-NMR (300 MHz, CD₂Cl₂): δ=0.04 ppm (s, 12H); 0.53 (s, 3H); 0.84 (s,18H); 1.02/1.03 (2×s, 3H); 1.05/1.06 (2×s, 3H); 1.93/1.94 (2×s, 3H);2.90/2.94 (2×d, OH); 4.04/4.09 (2×t, 1H); 4.16 (m, 1H); 4.35 (m, 1H);4.82 (brs, 1H); 5.17 (brs, 1H); 5.29/5.30 (2×dd, 1H); 5.79 (d, 1H); 5.98(d, 1H); 6.22 (d, 1H)

e) 160 mg of 32 is treated analogously to 1e), and, after chromatographyon silica gel with ethyl acetate/hexane as well as diastereomericseparation by HPLC on a chiral phase with hexane/isopropanol/ethanol insuccession, 12 mg of 33b and 21 mg of 33a are obtained as colorlessfoams.

¹H-NMR (300 MHz, CD₂Cl₂):

33b δ=0.56 ppm (s, 3H); 1.02 (s, 3H); 1.07 (s, 3H); 1.95 (s, 3H); 3.00(d, OH); 4.08 (m, 1H); 4.17 (m, 1H); 4.38 (m, 1H); 4.95 (brs, 1H); 5.29(brs, 1H); 5.30 (dd, 1H); 5.80 (d, 1H); 5.99 (d, 1H); 6.35 (d, 1H)

33a δ=0.57 ppm (s, 3H); 1.01 (s, 3H); 1.08 (s, 3H); 1.95 (s, 3H); 2.95(d, OH); 4.13 (m, 1H); 4.16 (m, 1H); 4.38 (m, 1H); 4.96 (brs, 1H); 5.29(brs, 1H); 5.30 (dd, 1H); 5.82 (d, 1H); 5.99 (d, 1H); 6.35 (d, 1H)

EXAMPLE 20(5Z,7E,22E)-(1S,3R,24R)-20-Methyl-25-(1-oxobutyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(35b) and(5Z,7E,22E)-(1S,3R,24S)-20-methyl-25-(1-oxobutyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(35a)

a) 0.9 ml of propyl iodide in 20 ml of diethyl ether is introduced, and8 ml of t-butyllithium solution (1.5 M in pentane) is added in drops at−78° C. under argon. This mixture is stirred for 30 minutes at −78° C.,and then added in drops to a solution of 300 mg of 31 in 2 ml of diethylether at −78° C. under argon. It is now stirred for 3 hours at −78° C.and then quenched with sodium chloride solution. It is then extractedwith ethyl acetate, the combined organic phases are washed with sodiumchloride solution, dried on sodium sulfate, and the solvent is removed.The residue is chromatographed on silica gel with ethyl acetate/hexane,whereby 180 mg of(5Z,7E,22E)-(1S,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-20-methyl-25-(1-oxobutyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen-24-ol34 accumulates as a colorless foam.

¹H-NMR (300 MHz, CD₂Cl₂): δ=0.03 ppm (s, 12H); 0.53 (s, 3H); 0.86 (s,18H); 0.86 (t, 3H); 1.00/1.01 (2×s, 3H); 1.05/1.06 (2×s, 3H); 2.14 (t,2H); 3.02/3.07 (2×d, OH); 4.02/4.05 (2×t, 1H); 4.17 (m, 1H); 4.37 (m,1H); 4.83 (brs, 1H); 5.17 (brs, 1H); 5.29/5.30 (2×dd, 1H); 5.78 (d, 1H);5.98 (d, 1H); 6.23 (d, 1H)

b) 160 mg of 34 is treated analogously to 1e), and, after chromatographyon silica gel with ethyl acetate/hexane as well as diastereomericseparation by HPLC on a chiral phase with hexane/isopropanol/ethanol insuccession, 14 mg of 35b and 27 mg of 35a are obtained as colorlessfoams.

¹H-NMR (300 MHz, CD₂Cl₂):

35b δ=0.55 ppm (s, 3H); 0.88 (t, 3H); 1.02 (s, 3H); 1.07 (s, 3H); 2.14(t, 2H); 3.10 (brs, OH); 4.05 (m, 1H); 4.17 (m, 1H); 4.38 (m, 1H); 4.95(brs, 1H); 5.29 (brs, 1H); 5.30 (dd, 1H); 5.79 (d, 1H); 5.99 (d, 1H);6.35 (d, 1H)

35a δ=0.55 ppm (s, 3H); 0.88 (t, 3H); 1.00 (s, 3H); 1.09 (s, 3H); 2.16(t, 2H); 3.06 (brs, OH); 4.08 (m, 1H); 4.17 (m, 1H); 4.37 (m, 1H); 4.95(brs, 1H); 5.29 (brs, 1H); 5.30 (dd, 1H); 5.81 (d, 1H); 5.99 (d, 1H);6.35 (d, 1H)

EXAMPLE 21(5Z,7E,22E)-(1S,3R,24R)-20-Methyl-25-(1-oxopentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(37b) and(5Z,7E,22E)-(1S,3R,24S)-20-methyl-25-(1-oxopentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(37a)

a) 250 mg of 31 in 10 ml of THF is introduced under argon and cooled to−78° C. At this temperature, 1 ml of n-butyllithium solution (1.6 M inhexane) is added in drops and stirred for 4 more hours. It is thenquenched with sodium chloride solution, extracted with ethyl acetate,dried on sodium sulfate, the solvent is removed, and the residue ischromatographed on silica gel with ethyl acetate/hexane, whereby 160 mgof(5Z,7E,22E)-(1S,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-20-methyl-25-(1-oxopentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen-24-ol36 is obtained as a colorless foam.

¹H-NMR (300 MHz, CDCl₃): δ=0.05 ppm (s, 12H); 0.54 (s, 3H); 0.88 (s,18H); 0.90 (t, 3H); 1.02/1.03 (2×s, 3H); 1.07/1.08 (2×s, 3H); 3.27/3.28(2×d, OH); 4.08 (m, 1H); 4.20 (m, 1H); 4.38 (m, 1H); 4.87 (brs, 1H);5.19 (brs, 1H); 5.32/5.33 (2×dd, 1H); 5.80 (d, 1H); 5.99 (d, 1H); 6.22(d, 1H)

b) 150 mg of 36 is treated analogously to 1e), and, after chromatographyon silica gel with ethyl acetate/hexane as well as diastereomericseparation by HPLC on a chiral phase with hexane/isopropanol/ethanol insuccession, 12 mg of 37b and 22 mg of 37a are obtained as colorlessfoams.

¹H-NMR (300 MHz, CD₂Cl₂):

37b δ=0.55 ppm (s, 3H); 0.89 (t, 3H); 1.01 (s, 3H); 1.07 (s, 3H); 2.18(t, 2H); 3.09 (d, OH); 4.04 (t, 1H); 4.17 (m, 1H); 4.38 (m, 1H); 4.96(brs, 1H); 5.30 (brs, 1H); 5.31 (dd, 1H); 5.80 (d, 1H); 5.99 (d, 1H);6.35 (d, 1H)

37a δ=0.56 ppm (s, 3H); 0.88 (t, 3H); 1.00 (s, 3H); 1.08 (s, 3H); 2.19(t, 2H); 2.99 (d, OH); 4.08 (m, 1H); 4.17 (m, 1H); 4.38 (m, 1H); 4.96(brs, 1H); 5.30 (brs, 1H); 5.31 (dd, 1H); 5.82 (d, 1H); 5.99 (d, 1H);6.35 (d, 1H)

EXAMPLE 22(5Z,7E,22E)-(1S,3R,24R)-20-Methyl-25-(1-oxohexyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(39b)

a) Analogously to 20a), 150 mg of 31 is reacted with 1-pentyllithium(that consists of 1-iodopentane and t-butyllithium), whereby 170 mg of(5Z,7E,22E)-(1S,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-20-methyl-25-(1-oxohexyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen-24-ol38 is obtained as a colorless foam. The separation of the diastereomerswas carried out by repeated chromatography on aluminum oxide plates withethyl acetate/hexane. 25 mg of(5Z,7E,22E)-(1S,3R,24R)-1,3-bis[[dimethyl(1,1-dimethylethyl)-silyl]oxy]-20-methyl-25-(1-oxohexyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen-24-ol38b and 18 mg of(5Z,7E,22E)-(1S,3R,24S)-1,3-bis[[dimethyl(1,1-dimethylethyl)-silyl]oxy]-20-methyl-25-(1-oxohexyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen-24-ol38a were obtained as colorless foams.

¹H-NMR (300 MHZ, CDCl₃):

38b δ=0.06 ppm (s, 12H); 0.53 (s, 3H); 0.87 (t, 3H); 0.88 (s, 18H); 0.99(s, 3H); 1.05 (s, 3H); 3.09 (d, OH); 4.02 (t, 1H); 4.18 (m, 1H); 4.39(m, 1H); 4.83 (brs, 1H); 5.19 (brs, 1H); 5.31 (dd, 1H); 5.79 (d, 1H);5.99 (d, 1H); 6.22 (d, 1H)

38a δ=0.06 ppm (s, 12H); 0.52 (s, 3H); 0.87 (t, 3H); 0.88 (s, 18H); 0.99(s, 3H); 1.08 (s, 3H); 3.03 (d, OH); 4.06 (t, 1H); 4.18 (m, 1H); 4.38(m, 1H); 4.83 (brs, 1H); 5.19 (brs, 1H); 5.30 (dd, 1H); 5.79 (d, 1H);5.99 (d, 1H); 6.23 (d, 1H)

b) 24 mg of 38b is treated analogously to 1e), and, after chromatographyon silica gel with ethyl acetate/hexane, 6 mg of 39b is obtained as acolorless foam.

¹H-NMR (300 MHz, CD₂Cl₂): δ=0.55 ppm (s, 3H); 0.88 (t, 3H); 1.00 (s,3H); 1.08 (s, 3H); 3.10 (brs, OH); 4.03 (m, 1H); 4.18 (m, 1H); 4.38 (m,1H); 4.94 (brs, 1H); 5.29 (brs, 1H); 5.29 (dd, 1H); 5.79 (d, 1H); 5.99(d, 1H); 6.34 (d, 1H)

EXAMPLE 23(5Z,7E,22E)-(1S,3R,24S)-20-Methyl-25-(1-oxohexyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(39a)

17 mg of 38a is treated analogously to 1e), and, after chromatography onsilica gel with ethyl acetate/hexane, 5 mg of 39a is obtained as acolorless foam.

¹H-NMR (300 MHz, CD₂Cl₂): δ=0.56 ppm (s, 3H); 0.87 (t, 3H); 1.00 (s,3H); 1.07 (s, 3H); 3.05 (brs, OH); 4.07 (m, 1H); 4.18 (m, 1H); 4.37 (m,1H); 4.95 (brs, 1H); 5.29 (brs, 1H); 5.29 (dd, 1H); 5.80 (d, 1H); 5.98(d, 1H); 6.35 (d, 1H)

EXAMPLE 24(5Z,7E,22E)-(1S,3R,24R)-20-Methyl-25-(1-oxoheptyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(41b) and(5Z,7E,22E)-(1S,3R,24S)-20-methyl-25-(1-oxoheptyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(41a)

a) Analogously to 20a), 300 mg of 31 is reacted with 1-hexyllithium(that consists of 1-iodohexane and t-butyllithium), whereby 150 mg of(5Z,7E,22E)-(1S,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-20-methyl-25-(1-oxoheptyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen-24-ol40 in addition to 230 mg of the starting material are obtained ascolorless foams.

¹H-NMR (300 MHz, CDCl₃): δ=0.06 ppm (s, 12H); 0.53 (s, 3H); 0.87 (t,3H); 0.89 (s, 18H); 1.02/1.03 (2×s, 3H); 1.08/1.09 (2×s, 3H); 3.25/3.29(2×d, OH); 4.06/4.08 (2×t, 1H); 4.19 (m, 1H); 4.38 (m, 1H); 4.87 (brs,1H); 5.20 (brs, 1H); 5.32/5.34 (dd, 1H); 5.80 (d, 1H); 5.99 (d, 1H);6.22 (d, 1H)

b) 145 mg of 40 is treated analogously to 1e), and, after chromatographyon silica gel with ethyl acetate/hexane as well as diastereomericseparation by HPLC on a chiral phase with hexane/isopropanol/ethanol insuccession, 19 mg of 41b and 11 mg of 41a are obtained as colorlessfoams.

¹H-NMR (300 MHz, CD₂Cl₂):

41b δ=0.55 ppm (s, 3H); 0.89 (t, 3H); 1.01 (s, 3H); 1.07 (s, 3H); 2.17(t, 2H); 3.10 (d, OH); 4.03 (t, 1H); 4.17 (m, 1H); 4.38 (m, 1H); 4.95(brs, 1H); 5.29 (brs, 1H); 5.30 (dd, 1H); 5.79 (d, 1H); 5.99 (d, 1H);6.35 (d, 1H)

41a δ=0.55 ppm (s, 3H); 0.88 (t, 3H); 1.00 (s, 3H); 1.07 (s, 3H); 2.17(t, 2H); 3.07 (brs, OH); 4.08 (m, 1H); 4.17 (m, 1H); 4.38 (m, 1H); 4.94(brs, 1H); 5.28 (brs, 1H); 5.30 (dd, 1H); 5.80 (d, 1H); 5.99 (d, 1H);6.35 (d, 1H)

EXAMPLE 25(5Z,7E,22E)-(1S,3R,24R)-20-Methyl-25-(1-oxooctyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(43b) and(5Z,7E,22E)-(1S,3R,24S)-20-methyl-25-(1-oxooctyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24,triol(43a)

a) Analogously to 20a), 300 mg of 31 is reacted with 1-heptyllithium(that consists of 1-iodoheptane and t-butyllithium), whereby 160 mg of(5Z,7E,22E)-(1S,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-20-methyl-25-(1-oxooctyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen-24-ol42 in addition to 210 mg of the starting material are obtained ascolorless foams.

¹H-NMR (300 MHz, CDCl₃): δ=0.06 ppm (s, 12H); 0.52 (s, 3H); 0.88 (t,3H); 0.89 (s, 18H); 1.00/1.01 (2×s, 3H); 1.05/1.06 (2×s, 3H); 3.21/3.28(2×d, OH); 4.04/4.07 (2×t, 1H); 4.18 (m, 1H); 4.37 (m, 1H); 4.85 (brs,1H); 5.18 (brs, 1H); 5.31/5.32 (dd, 1H); 5.79 (d, 1H); 5.98 (d, 1H);6.21 (d, 1H)

b) 155 mg of 42 is treated analogously to 1e), and, after chromatographyon silica gel with ethyl acetate/hexane as well as diastereomericseparation by HPLC on a chiral phase with hexane/isopropanol/ethanol insuccession, 31 mg of 43b and 25 mg of 43a are obtained as colorlessfoams.

¹H-NMR (300 MHz, CD₂Cl₂):

43b δ=0.55 ppm (s, 3H); 0.88 (t, 3H); 1.01 (s, 3H); 1.06 (s, 3H); 2.17(t, 2H); 3.12 (d, OH); 4.03 (t, 1H); 4.17 (m, 1H); 4.37 (m, 1H); 4.95(brs, 1H); 5.29 (brs, 1H); 5.32 (dd, 1H); 5.80 (d, 1H); 5.99 (d, 1H);6.34 (d, 1H)

43a δ=0.54 ppm (s, 3H); 0.87 (t, 3H); 0.99 (s, 3H); 1.07 (s, 3H); 2.17(t, 2H); 3.04 (brs, OH); 4.07 (m, 1H); 4.17 (m, 1H); 4.37 (m, 1H); 4.95(brs, 1H); 5.29 (brs, 1H); 5.31 (dd, 1H); 5.80 (d, 1H); 5.99 (d, 1H);6.34 (d, 1H)

EXAMPLE 26(7E,22E)-(1R,3R,24R)-25-Acetyl-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(55b)

a) 6.70 g of[1R-[1α(S*),3aβ,4α,7aα]]-α,7a-dimethyloctahydro-4-[(triethylsilyl)oxy]-1H-inden-1-acetaldehyde44 [H. H. Inhoffen et al. Chem. Ber. 91, 780 (1958), Chem. Ber. 92, 1772(1959), W. G. Dauben et al. Tetrahedron Lett. 30, 677 (1989),Triethylsilyl Protective Group at C-4-OH] is reacted analogously to19a), and 11.6 g of[1R-[1α[R*-(E)],3aβ,4α,7aα]]-1-[4-[7a-methyloctahydro-4-[(triethylsilyl)oxy]-1H-inden-1-yl]-1-oxo-2-pentenyl]cyclopropanecarboxylicacid 45 is obtained as a yellow oil.

b) 15 g of crude product 45 is reacted analogously to 19b), and 11.9 gof[1R-[1α[R*-(E)],3aβ,4α,7aα]]-N,N-dimethyl-1-[4-[7a-methyloctahydro-4-[(triethylsilyl)oxy]-1H-inden-1-yl]-1-oxo-2-pentenyl]cyclopropanecarboxylicacid amide 46 is obtained as a colorless oil.

¹H-NMR (300 MHz, CDCl₃): δ=0.52 ppm (q, 6H); 0.92 (s, 3H); 0.93 (t, 9H);2.95 (s, 3H); 3.00 (s, 3H); 4.01 (s, 1H); 6.15 (d, 1H); 6.82 (d, 1H)

c) 11.6 g of 46 is reacted analogously to 1b), and 8.7 g of[1R-[1α[R*-(E)],3aβ,4α,7aα]]-N,N-dimethyl-1-[1-hydroxy-4-[7a-methyloctahydro-4-[(triethylsilyl)oxy]-1H-inden-1-yl]-2-pentenyl]cyclopropanecarboxylicacid amide 47 is obtained as a colorless oil.

¹H-NMR (300 MHz, CDCl₃): δ=0.54 ppm (q, 6H); 0.89 (s, 3H); 0.94 (t, 9H);2.62 (brd, OH); 3.04 (brs, 6H); 4.02 (s, 1H); 5.27/5.29 (2×dd, 1H);5.51/5.54 (2×dd, 1H)

d) 5.34 g of 47 in 70 ml of methylene chloride is stirred with 3.2 ml ofdihydropyran and 187 mg of pyridinium-p-toluenesulfonate under argon atroom temperature for 3 days. Then, sodium chloride solution is added,extracted with methylene chloride, the combined organic phases arewashed with sodium bicarbonate solution and sodium chloride solution,dried on sodium sulfate and liberated of solvent. The residue ischromatographed on silica gel with ethyl acetate/hexane, whereby 4.91 gof[1R-[1α[R*-(E)],3aβ,4α,7aα]]-N,N-dimethyl-1-[4-[7a-methyloctahydro-4-[(triethylsilyl)oxy]-1H-inden-1-yl]-1-[(tetrahydro-2H-pyran-2-yl)oxy]-2-pentenyl]cyclopropanecarboxylicacid amide 48 is obtained as a colorless oil.

e) 5.92 g of 48 is treated analogously to 1e), and 2.99 g of[1R-[1α[R*-(E)],3aβ,4α,7aα]]-N,N-dimethyl-1-[4-(4-hydroxy-7a-methyloctahydro-1H-inden-1-yl)-1-[(tetrahydro-2H-pyran-2-yl)oxy]-2-pentenyl]cyclopropanecarboxylicacid amide 49 is obtained as a colorless oil.

f) 2.67 g of 49 is dissolved in 130 ml of methylene chloride, 1.87 g ofpyridinium chlorochromate is added in portions and stirred for 2 hoursunder argon at room temperature. Then, it is diluted with diethyl ether,filtered, and the solvent is removed. The residue is chromatographed onsilica gel with ethyl acetate/hexane, whereby 2.84 g of[1R-[1α[R*-(E)],3aβ,7aα]]-N,N-dimethyl-1-[4-(7a-methyloctahydro-4-oxo-1H-inden-1-yl)-1-[(tetrahydro-2H-pyran-2-yl)oxy]-2-pentenyl]cyclopropanecarboxylicacid amide 50 is obtained as a colorless oil.

g) 1.0 g of(3R-trans)-[2-[3,5-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]cyclohexylidene]ethyl]diphenylphosphineoxide 51 [H. F. DeLuca et al. Tetrahedron Lett. 32, 7663 (1991)] in 10ml of THF is dissolved and cooled under argon to −78° C. 2.1 ml ofn-butyllithium solution (2.5 M in hexane) is now added in drops andstirred for 5 more minutes. Then, 381 mg of 50 in 7 ml of THF is addedand stirred for 30 minutes at −78° C. Then, it is quenched withpotassium/sodium tartrate solution, extracted with ethyl acetate, theorganic phase is washed with sodium chloride solution, dried on sodiumsulfate, and the solvent is removed. The residue is chromatographed onsilica gel with ethyl acetate/hexane, whereby 648 mg of(7E,22E)-(1R,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-N,N-dimethyl-24ξ-[(tetrahydro-2H-pyran-2-yl)oxy]-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-25-carboxylicacid amide 52 remains as a colorless foam.

h) 350 mg of 52 is dissolved in 5 ml of THF, and 0.64 ml ofmethyllithium solution (1.3 M in diethyl ether) is added in drops at−78° C. under argon. After 90 minutes, it is quenched with sodiumchloride solution, extracted with ethyl acetate, the organic phase iswashed with sodium chloride solution, dried on sodium sulfate, and thesolvent is removed. The residue is chromatographed on silica gel withethyl acetate/hexane, whereby 284 mg of(7E,22E)-(1R,3R)-25-acetyl-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-24ξ-[(tetrahydro-2H-pyran-2-yl)oxy]-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene53 remains as a colorless foam.

i) 279 mg of 53 is dissolved in 37 ml of methylene chloride and treatedat −25° C. under argon with 0.74 ml of dimethylaluminum chloridesolution (1 M in hexane). It is stirred for 10 hours at thistemperature, and the batch is optionally put overnight in a freezer.Then, it is hydrolyzed with sodium bicarbonate solution, extracted withmethylene chloride, the organic phase is washed with sodium chloridesolution, dried on sodium sulfate, the solvent is removed, and theresidue is chromatographed on silica gel with ethyl acetate/hexane. Theseparation of the diastereomeric alcohols (relative to C-24) was carriedout on aluminum oxide plates with ethyl acetate/hexane. Thus, 69 mg of(7E,22E)-(1R,3R,24S)-25-acetyl-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-trien-24-ol54a in addition to 36 mg of(7E,22E)-(1R,3R,24R)-25-acetyl-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-trien-24-ol54b are obtained as colorless foams.

¹H-NMR (300 MHz, CD₂Cl₂):

54a δ=0.05 ppm (s, 12H); 0.52 (s, 3H); 0.85 (s, 18H); 1.01 (d, 3H); 1.93(s, 3H); 2.89 (d, OH); 4.07 (m, 2H); 4.16 (t, 1H); 5.34 (dd, 1H); 5.52(dd, 1H); 5.80 (d, 1H); 6.16 (d, 1H)

54b δ=0.05 ppm (s, 12H); 0.52 (s, 3H); 0.85 (s, 18H); 1.02 (d, 3H); 1.93(s, 3H); 2.95 (d, OH); 4.06 (m, 3H); 5.33 (dd, 1H); 5.46 (dd, 1H); 5.80(d, 1H); 6.16 (d, 1H)

j) 36 mg of 54b is treated analogously to 1e), and, after chromatographyon silica gel with ethyl acetate/hexane, 20 mg of 55b is obtained as acolorless foam.

¹H-NMR (300 MHz, CD₂Cl₂/CD₃OD): δ=0.53 ppm (s, 3H); 1.01 (s, 3H); 1.98(s, 3H); 3.94 (m, 1H); 4.01 (m, 1H); 4.15 (m, 1H); 5.29 (dd, 1H); 5.47(dd, 1H); 5.83 (d, 1H); 6.23 (d, 1H)

EXAMPLE 27(7E,22E)-(1R,3R,24S)-25-Acetyl-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(55a)

a) 69 mg of 54a is treated analogously to 1e), and, after chromatographyon silica gel with ethyl acetate/hexane, 25 mg of 55a is obtained as acolorless foam.

¹H-NMR (300 MHz, CD₂Cl₂/CD₃OD): δ=0.53 ppm (s, 3H); 0.99 (s, 3H); 1.98(s, 3H); 3.96 (m, 1H); 4.01 (m, 1H); 4.20 (t, 1H); 5.30 (dd, 1H); 5.50(dd, 1H); 5.83 (d, 1H); 6.23 (d, 1H)

EXAMPLE 28(7E,22E)-(1R,3R,24R)-25-(1-Oxopentyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(58b)

a) 420 mg of 52 is treated analogously to 21a), and, afterchromatography on silica gel with ethyl acetate/hexane, 250 mg of(7E,22E)-(1R,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-(1-oxopentyl)-24ξ-[(tetrahydro-2H-pyran-2-yl)oxy]-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene56 is obtained as a colorless foam.

b) 232 mg of 56 is treated analogously to 26i), and, afterchromatography on silica gel with ethyl acetate/hexane together, 64 mgof(7E,22E)-(1R,3R,24S)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-(1-oxopentyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-trien-24-ol57a in addition to 42 mg of(7E,22E)-(1R,3R,24R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-(1-oxopentyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-trien-24-ol57b are obtained as colorless foams.

¹H-NMR (300 MHz, CD₂Cl₂):

57a δ=0.04 ppm (s, 12H); 0.52 (s, 3H); 0.85 (s, 18H); 0.87 (t, 3H); 1.01(d, 3H); 3.00 (d, OH); 4.04 (m, 2H); 4.12 (t, 1H); 5.32 (dd, 1H); 5.51(dd, 1H); 5.81 (d, 1H); 6.15 (d, 1H)

57b δ=0.04 ppm (s, 12H); 0.52 (s, 3H); 0.85 (s, 18H); 0.87 (t, 3H); 1.01(d, 3H); 3.05 (d, OH); 4.05 (m, 3H); 5.34 (dd, 1H); 5.44 (dd, 1H); 5.81(d, 1H); 6.15 (d, 1H)

c) 41 mg of 57b is treated analogously to 1e), and 15 mg of 58b isobtained as a colorless foam.

¹H-NMR (300 MHz, CD₂Cl₂/CD₃OD): δ=0.52 ppm (s, 3H); 0.89 (t, 3H); 1.00(d, 3H); 2.27 (t, 2H); 3.95 (m, 1H); 4.03 (m, 1H); 4.17 (t, 1H); 5.31(dd, 1H); 5.48 (dd, 1H); 5.82 (d, 1H); 6.22 (d, 1H)

EXAMPLE 29(7E,22E)-(1R,3R,24S)-25-(1-Oxopentyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(58a)

62 mg of 57a is treated analogously to 1e), and 27 mg of 58a is obtainedas a colorless foam.

¹H-NMR (300 MHz, CD₂Cl₂/CD₃OD): δ=0.51 ppm (s, 3H); 0.87 (t, 3H); 0.99(d, 3H); 2.23 (t, 2H); 3.95 (m, 1H); 4.02 (m, 1H); 4.19 (t, 1H); 5.32(dd, 1H); 5.50 (dd, 1H); 5.82 (d, 1H); 6.23 (d, 1H)

EXAMPLE 30(7E,22E)-(1R,3R,24R)-25-(1-Oxohexyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(61b)

a) Analogously to 20a), 500 mg of 52 is reacted with 1-pentyllithium(that consists of 1-iodopentane and t-butyllithium), whereby afterchromatography with ethyl acetate/hexane, 321 mg of(7E,22E)-(1R,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-(1-oxohexyl)-24ξ-[(tetrahydro-2H-pyran-2-yl)oxy]-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene59 is obtained as a colorless foam.

b) 213 mg of 59 is treated analogously to 26i), and, afterchromatography on silica gel with ethyl acetate/hexane together, 81 mgof(7E,22E)-(1R,3R,24S)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-(1-oxohexyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-trien-24-ol60a in addition to 42 mg of(7E,22E)-(1R,3R,24R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-(1-oxohexyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-trien-24-ol60b are obtained as colorless foams.

₁H-NMR (300 MHz, CD₂Cl₂):

60a δ=0.04 ppm (s, 12H); 0.52 (s, 3H); 0.86 (s, 18H); 0.87 (t, 3H); 1.01(d, 3H); 2.15 (t, 2H); 3.01 (d, OH); 4.05 (m, 2H); 4.12 (t, 1H); 5.33(dd, 1H); 5.51 (dd, 1H); 5.81 (d, 1H); 6.15 (d, 1H)

60b δ=0.04 ppm (s, 12H); 0.52 (s, 3H); 0.86 (s, 18H); 0.87 (t, 3H); 1.02(d, 3H); 2.15 (t, 2H); 3.07 (d, OH); 4.02 (t, 1H); 4.06 (m, 2H); 5.34(dd, 1H); 5.44 (dd, 1H); 5.81 (d, 1H); 6.15 (d, 1H)

c) 51 mg of 60b is treated analogously to 1e), and 27 mg of 61b isobtained as a colorless foam.

¹H-NMR (300 MHz, CD₂Cl₂): δ=0.54 ppm (s, 3H); 0.87 (t, 3H); 1.02 (d,3H); 2.16 (t, 2H); 3.11 (d, OH); 3.95 (m, 1H); 4.03 (m, 1H); 4.05 (t,1H); 5.34 (dd, 1H); 5.46 (dd, 1H); 5.83 (d, 1H); 6.24 (d, 1H)

EXAMPLE 31(7E,22E)-(1R,3R,24S)-25-(1-Oxohexyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(61a)

63 mg of 60a is treated analogously to 1e), and 32 mg of 61a is obtainedas a colorless foam.

¹H-NMR (300 MHz, CD₂Cl₂): δ=0.54 ppm (s, 3H); 0.87 (t, 3H); 1.01 (d,3H); 2.16 (t, 2H); 3.04 (d, OH); 3.95 (m, 1H); 4.03 (m, 1H); 4.13 (t,1H); 5.34 (dd, 1H); 5.51 (dd, 1H); 5.83 (d, 1H); 6.24 (d, 1H)

EXAMPLE 32(7E,22E)-(1R,3R,24R)-25-(1-Oxoheptyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(64b)

a) Analogously to 20a), 500 mg of 52 is reacted with 1-hexyllithium(that consists of 1-iodohexane and t-butyllithium), whereby afterchromatography with ethyl acetate/hexane, 255 mg of(7E,22E)-(1R,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-(1-oxoheptyl)-24ξ-[(tetrahydro-2H-pyran-2-yl)oxy]-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene62 is obtained as a colorless foam.

b) 190 mg of 62 is treated analogously to 26i), and, afterchromatography on silica gel with ethyl acetate/hexane together, 53 mgof(7E,22E)-(1R,3R,24S)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-(1-oxoheptyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-trien-24-ol63a in addition to 29 mg of(7E,22E)-(1R,3R,24R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-(1-oxoheptyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-trien-24-ol63b are obtained as colorless foams.

¹H-NMR (300 MHz, CD₂Cl₂):

63a δ=0.03 ppm (s, 12H); 0.53 (s, 3H); 0.85 (s, 18H); 0.87 (t, 3H); 1.01(d, 3H); 2.16 (t, 2H); 3.00 (d, OH); 4.05 (m, 2H); 4.12 (t, 1H); 5.32(dd, 1H); 5.51 (dd, 1H); 5.81 (d, 1H); 6.14 (d, 1H)

63b δ=0.03 ppm (s, 12H); 0.53 (s, 3H); 0.85 (s, 18H); 0.87 (t, 3H); 1.02(d, 3H); 2.16 (t, 2H); 3.05 (d, OH); 4.03 (t, 1H); 4.05 (m, 2H); 5.34(dd, 1H); 5.44 (dd, 1H); 5.81 (d, 1H); 6.14 (d, 1H)

c) 29 mg of 63b is treated analogously to 1e), and 17 mg of 64b isobtained as a colorless foam.

¹H-NMR (300 MHz, CD₂Cl₂): δ=0.53 ppm (s, 3H); 0.88 (t, 3H); 1.03 (d,3H); 2.17 (t, 2H); 3.12 (d, OH); 3.98 (m, 1H); 4.05 (m, 1H); 4.08 (t,1H); 5.35 (dd, 1H); 5.48 (dd, 1H); 5.84 (d, 1H); 6.26 (d, 1H)

EXAMPLE 33(7E,22E)-(1R,3R,24S)-25-(1-Oxoheptyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(64a)

52 mg of 63a is treated analogously to 1e), and 27 mg of 64a is obtainedas a colorless foam.

¹H-NMR (300 MHz, CD₂Cl₂): δ=0.53 ppm (s, 3H); 0.88 (t, 3H); 1.02 (d,3H); 2.16 (t, 2H); 3.08 (d, OH); 3.98 (m, 1H); 4.05 (m, 1H); 4.12 (t,1H); 5.33 (dd, 1H); 5.51 (dd, 1H); 5.84 (d, 1H); 6.27 (d, 1H)

EXAMPLE 34(7E,22E)-(1R,3R,24R)-25-(1-Oxooctyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(67b)

a) Analogously to 20a), 380 mg of 52 is reacted with 1-heptyllithium(that consists of 1-iodoheptane and t-butyllithium), whereby afterchromatography with ethyl acetate/hexane, 224 mg of(7E,22E)-(1R,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-(1-oxooctyl)-24ξ-[(tetrahydro-2H-pyran-2-yl)oxy]-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene65 is obtained as a colorless foam.

b) 103 mg of 65 is treated analogously to 26i), and, afterchromatography on silica gel with ethyl acetate/hexane together, 28 mgof(7E,22E)-(1R,3R,24S)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-(1-oxooctyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-trien-24-ol66a in addition to 24 mg of(7E,22E)-(1R,3R,24R)-1,3-Bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-(1-oxooctyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-trien-24-ol66b are obtained as colorless foams.

¹H-NMR (300 MHz, CD₂Cl₂):

66a δ=0.04 ppm (s, 12H); 0.53 (s, 3H); 0.85 (s, 18H); 0.86 (t, 3H); 1.00(d, 3H); 2.17 (t, 2H); 3.01 (d, OH); 4.06 (m, 2H); 4.12 (t, 1H); 5.32(dd, 1H); 5.51 (dd, 1H); 5.80 (d, 1H); 6.14 (d, 1H)

66b δ=0.04 ppm (s, 12H); 0.53 (s, 3H); 0.85 (s, 18H); 0.86 (t, 3H); 1.02(d, 3H); 2.15 (t, 2H); 3.05 (d, OH); 4.02 (t, 1H); 4.06 (m, 2H); 5.35(dd, 1H); 5.45 (dd, 1H); 5.80 (d, 1H); 6.14 (d, 1H)

c) 24 mg of 66b is treated analogously to 1e), and 10 mg of 67b isobtained as a colorless foam.

¹H-NMR (300 MHz, CD₂Cl₂): δ=0.53 ppm (s, 3H); 0.87 (t, 3H); 1.01 (d,3H); 2.17 (t, 2H); 3.08 (brs, OH); 3.98 (m, 1H); 4.06 (m, 2H); 5.36 (dd,1H); 5.48 (dd, 1H); 5.83 (d, 1H); 6.27 (d, 1H)

EXAMPLE 35(7E,22E)-(1R,3R,24S)-25-(1-Oxooctyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(67a)

38 mg of 66a is treated analogously to 1e), and 13 mg of 67a is obtainedas a colorless foam.

¹H-NMR (300 MHz, CD₂Cl₂): δ=0.53 ppm (s, 3H); 0.85 (t, 3H); 1.00 (d,3H); 2.15 (t, 2H); 3.00 (brs, OH); 3.97 (m, 1H); 4.06 (m, 1H); 4.11 (t,1H); 5.35 (dd, 1H); 5.50 (dd, 1H); 5.83 (d, 1H); 6.26 (d, 1H)

EXAMPLE 36(7E,22E)-(1R,3R,24R)-25-(1-Oxononyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(70b)

a) Analogously to 20a), 375 mg of 52 is reacted with 1-octyllithium(that consists of 1-iodooctane and t-butyllithium), whereby afterchromatography with ethyl acetatehexane, 212 mg of(7E,22E)-(1R,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-(1-oxononyl)-24ξ-[(tetrahydro-2H-pyran-2-yl)oxy]-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene68 is obtained as a colorless foam.

b) 125 mg of 68 is treated analogously to 26i), and, afterchromatography on silica gel with ethyl acetate/hexane together, 36 mgof(7E,22E)-(1R,3R,24S)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-(1-oxononyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-trien-24-ol69a in addition to 24 mg of(7E,22E)-(1R,3R,24R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-(1-oxononyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-trien-24-ol69b are obtained as colorless foams.

¹H-NMR (300 MHz, CD₂Cl₂):

69a δ=0.05 ppm (s, 12H); 0.52 (s, 3H); 0.85 (s, 18H); 0.86 (t, 3H); 1.01(d, 3H); 2.16 (t, 2H); 3.02 (d, OH); 4.05 (m, 2H); 4.12 (t, 1H); 5.32(dd, 1H); 5.51 (dd, 1H); 5.80 (d, 1H); 6.14 (d, 1H)

69b δ=0.05 ppm (s, 12H); 0.53 (s, 3H); 0.85 (s, 18H); 0.86 (t, 3H); 1.02(d, 3H); 2.16 (t, 2H); 3.05 (d, OH); 4.02 (t, 1H); 4.05 (m, 2H); 5.34(dd, 1H); 5.45 (dd, 1H); 5.80 (d, 1H); 6.14 (d, 1H)

c) 36 mg of 69b is treated analogously to 1e), and 17 mg of 70b isobtained as a colorless foam.

¹H-NMR (300 MHz, CD₂Cl₂): δ=0.54 ppm (s, 3H); 0.87 (t, 3H); 1.02 (d,3H); 2.16 (t, 2H); 3.08 (brs, OH); 3.98 (m, 1H); 4.05 (m, 2H); 5.35 (dd,1H); 5.48 (dd, 1H); 5.83 (d, 1H); 6.28 (d, 1H)

EXAMPLE 37(7E,22E)-(1R,3R,24S)-25-(1-Oxononyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(70a)

24 mg of 69a is treated analogously to 1e), and 8 mg of 70a is obtainedas a colorless foam.

¹H-NMR (300 MHz, CD₂Cl₂): δ=0.54 ppm (s, 3H); 0.87 (t, 3H); 1.02 (d,3H); 2.17 (t, 2H); 3.07 (d, OH); 3.98 (m, 1H); 4.05 (m, 1H); 4.12 (t,1H); 5.34 (dd, 1H); 5.51 (dd, 1H); 5.83 (d, 1H); 6.28 (d, 1H)

EXAMPLE 38(7E,22E)-(1R,3R,24S)-25-Acetyl-20-methyl-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(81a) and(7E,22E)-(1R,3R,24R)-25-acetyl-20-methyl-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(81b)

a) 1.8 g of sodium hydride (55% in mineral oil) in 105 ml of THF isintroduced under argon, and a solution of 10.8 g of[1R-[1α(S*),3aβ,4α,7aα]]-α,7a-dimethyloctahydro-4-[(triethylsilyl)oxy]-1H-inden-1-acetaldehyde44 [H. H. Inhoffen et al. Chem. Ber. 91, 780 (1958), Chem. Ber. 92, 1772(1959), W. G. Dauben et al. Tetrahedron Lett. 30, 677 (1989),Triethylsilyl Protective Group at C-4-OH] in 45 ml of THF is added indrops. Then, 6.24 ml of iodomethane is added in drops, and the mixtureis stirred overnight at room temperature. The reaction mixture is nowcarefully poured into ice water and extracted with ethyl acetate. Thecombined organic phases are washed with sodium chloride solution, driedon sodium sulfate, the solvent is removed, and the residue ischromatographed on silica gel with ethyl acetate/hexane, whereby 7.52 gof[1S-(1α,3aβ,4α,7aα)]-octahydro-4-[(triethylsilyl)oxy]-α,α,7a-trimethyl-1H-inden-1-acetaldehyde71.

¹H-NMR (300 MHz, CDCl₃): δ=0.57 ppm (q, 6H); 0.97 (t, 9H); 0.98 (s, 3H);1.10 (s, 3H); 1.12 (s, 3H); 4.05 (m, 1H); 9.68 (s, 1H)

b) 7.5 g of 71 is reacted analogously to 19a), and 14.6 g of[1R-[1α(E),3aβ,4α,7aα]]-1-[4-methyl-4-[7a-methyloctahydro-4-[(triethylsilyl)oxy]-1H-inden-1-yl]-1-oxo-2-pentenyl]cyclopropanecarboxylicacid 72 is obtained as a yellowish oil.

c) 12.9 g of 72 is reacted analogously to 19b), and 5.8 g of[1R-[1α(E),3aβ,4α,7aα]]-N,N-dimethyl-1-[4-methyl-4-[7a-methyloctahydro-4-[(triethylsilyl)oxy]-1H-inden-1-yl]-1-oxo-2-pentenyl]cyclopropanecarboxylicacid amide 73 is obtained as a colorless oil.

¹H-NMR (300 MHz, CDCl₃): δ=0.54 ppm (q, 6H); 0.92 (t, 9H); 0.93 (s, 3H);1.03 (s, 3H); 1.10 (s, 3H); 2.94 (s, 3H); 2.99 (s, 3H); 4.01 (m, 1H);6.15 (d, 1H); 7.22 (d, 1H)

d) 1.02 g of 73 is reacted analogously to 1b), and 743 mg of[1R-[1α(E),3aβ,4α,7aα]]-N,N-dimethyl-1-[1-hydroxy-4-methyl-4-[7a-methyloctahydro-4-[(triethylsilyl)oxy]-1H-inden-1-yl]-2-pentenyl]cyclopropanecarboxylicacid amide 74 is obtained as a colorless oil.

¹H-NMR (300 MHz, CDCl₃): δ=0.54 ppm (q, 6H); 0.92 (t, 9H); 0.94 (s, 3H);1.00/1.01 (2×s, 3H); 1.05, 1.06 (2×s, 3H); 3.03 (br s, 3H); 4.00 (m,1H); 4.05 (m, 1H); 5.22 (d, 1H); 5.89 (d, 1H)

e) 1.01 g of 74 is treated analogously to 26d), and 938 mg of[1R-[1α(E),3aβ,4α,7aα]]-N,N-dimethyl-1-[4-methyl-4-[7a-methyloctahydro-4-[(triethylsilyl)oxy]-1H-inden-1-yl]-1-[(tetrahydro-2H-pyran-2-yl)oxy]-2-pentenyl]cyclopropanecarboxylicacid amide 75 is obtained as a colorless oil.

f) 1.64 g of 75 is treated analogously to 1e), and 1.08 g of[1R-[1α(E),3aβ,4α,7aα]]-N,N-dimethyl-1-[4-(4-hydroxy-7a-methyloctahydro-1H-inden-1-yl)-4-methyl-1-[(tetrahydro-2H-pyran-2-yl)oxy]-2-pentenyl]cyclopropanecarboxylicacid amide 76 is obtained as a colorless oil.

g) 1.07 g of 76 is treated analogously to 26f), whereby 920 mg of[1R-[1α(E),3aβ,7aα]]-N,N-dimethyl-1-[4-methyl-4-(7a-methyloctahydro-4-oxo-1H-inden-1-yl)-1-[(tetrahydro-2H-pyran-2-yl)oxy]-2-pentenyl]cyclopropanecarboxylicacid amide 77 is obtained as a colorless foam.

h) Analogously to 26g), 583 mg of 77 is reacted with 1.5 g of(3R-trans)-[2-[3,5-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]cyclohexylidene]ethyl]diphenylphosphineoxide 51, and, after chromatographic purification on silica gel withhexane/ethyl acetate, 1.02 g of(7E,22E)-(1R,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-24ξ-[(tetrahydro-2H-pyran-2-yl)oxy]-N,N-20-trimethyl-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-25-carboxylicacid amide 78 is obtained as a colorless foam.

g) 254 mg of 78 is reacted with methyllithium analogously to 26h), and136 mg of(7E,22E)-(1R,3R)-25-acetyl-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-20-methyl-24ξ-[(tetrahydro-2H-pyran-2-yl)oxy]-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene79 is obtained as a colorless foam.

h) 135 mg of 79 is treated analogously to 26i), and 51 mg of(7E,22E)-(1R,3R)-25-acetyl-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-20-methyl-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-trien-24-ol80 is obtained as a colorless foam.

¹H-NMR (300 MHz, CDCl₃): δ=0.05 ppm (s, 12H); 0.54 (s, 3H); 0.87 (s,18H); 1.01/1.02 (2×s, 3H); 1.07/1.08 (2×s, 3H); 1.96/1.97 (2×s, 3H);3.11/3.15 (m, OH); 4.08 (m, 3H); 5.32/5.34 (2×dd, 1H); 5.78 (d, 1H);5.82 (d, 1H); 6.15 (d, 1H)

i) 50 mg of 80 is treated analogously to 1e), and, after chromatographyon silica gel with ethyl acetate/hexane as well as diastereomericseparation by HPLC on a chiral phase with hexane/isopropanol/ethanol insuccession, 4 mg of 81b and 5 mg of 81a are obtained as colorless foams.

¹H-NMR (300 MHz, CD₂Cl₂):

81b δ=0.55 ppm (s, 3H); 1.02 (s, 3H); 1.08 (s, 3H); 1.95 (s, 3H); 3.98(m, 1H); 4.07 (m, 1H); 4.08 (d, 1H); 5.31 (dd, 1H); 5.80 (d, 1H); 5.82(d, 1H); 6.28 (d, 1H)

81a δ=0.55 ppm (s, 3H); 1.01 (s, 3H); 1.08 (s, 3H); 1.96 (s, 3H); 2.94(brs, OH); 3.99 (m, 1H); 4.08 (m, 1H); 4.12 (d, 1H); 5.31 (dd, 1H); 5.82(d, 1H); 5.82 (d, 1H); 6.28 (d, 1H)

EXAMPLE 39(7E,22E)-(1R,3R,24S)-20-Methyl-25-(1-oxopentyl-26,27-(cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(84a) and(7E,22E)-(1R,3R,24R)-20-methyl-25-(1-oxopentyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(84b)

a) 250 mg of 78 is reacted analogously to 21a), and, afterchromatography on silica gel with ethyl acetate/hexane, 200 mg of(7E,22E)-(1R,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-20-methyl-25-(1-oxopentyl)-24ξ-[(tetrahydro-2H-pyran-2-yl)oxy]-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene82 is obtained as a colorless foam.

b) 195 mg of 82 is treated analogously to 26i), and 89 mg of(7E,22E)-(1R,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-20-methyl-25-(1-oxopentyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-trien-24-ol83 is obtained as a colorless foam.

¹H-NMR (300 MHz, CDCl₃): δ=0.06 ppm (s, 12H); 0.55 (s, 3H); 0.88 (s,18H); 0.90 (t, 3H); 1.01/1.02 (2×s, 3H); 1.07/1.08 (2×s, 3H); 2.14/2.15(2×t, 2H); 3.23/3.29 (2×d, OH); 4.08 (m, 3H); 5.33/5.34 (2×dd, 1H); 5.79(d, 1H); 5.82 (d, 1H); 6.16 (d, 1H)

c) 85 mg of 83 is treated analogously to 1e), and, after chromatographyon silica gel with ethyl acetate/hexane as well as diastereomericseparation by HPLC on a chiral phase with hexane/isopropanol/ethanol insuccession, 12 mg of 84b and 16 mg of 84a are obtained as colorlessfoams.

¹H-NMR (300 MHz, CD₂Cl₂):

84b δ=0.55 ppm (s, 3H); 0.91 (t, 3H); 1.03 (s, 3H); 1.09 (s, 3H); 2.20(t, 2H); 3.09 (d, OH); 4.00 (m, 1H); 4.07 (m, 2H); 5.31 (dd, 1H); 5.82(d, 1H); 5.83 (d, 1H); 6.28 (d, 1H)

84a δ=0.55 ppm (s, 3H); 0.91 (t, 3H); 1.02 (s, 3H); 1.10 (s, 3H); 2.20(t, 2H); 3.09 (d, OH); 4.00 (m, 1H); 4.08 (m, 1H); 4.10 (m, 1H); 5.31(dd, 1H); 5.82 (d, 1H); 5.82 (d, 1H); 6.28 (d, 1H)

EXAMPLE 40(7E,22E)-(1R,3R,24S)-20-Methyl1-25-(1-oxohexyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(87a) and(7E,22E)-(1R,3R,24R)-20-methyl-25-(1-oxohexyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(87b)

a) 250 mg of 78 is reacted analogously to 20a) with 1-pentyllithium(that consists of 1-iodopentane and t-butyllithium), and, afterchromatography on silica gel with ethyl acetate/hexane, 192 mg of(7E,22E)-(1R,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-20-methyl-25-(1-oxohexyl)-24ξ-[(tetrahydro-2H-pyran-2-yl)oxy]-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene85 is obtained as a colorless foam.

b) 187 mg of 85 is treated analogously to 26i), and 91 mg of(7E,22E)-(1R,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-20-methyl-25-(1-oxohexyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-trien-24-ol86 is obtained as a colorless foam.

¹H-NMR (300 MHz, CDCl₃): δ=0.06 ppm (s, 12H); 0.55 (s, 3H); 0.88 (s,18H); 0.89 (t, 3H); 1.01/1.02 (2×s, 3H); 1.07/1.08 (2×s, 3H); 2.14/2.15(2×t, 2H); 3.25/3.30 (2×d, OH); 4.08 (m, 3H); 5.34/5.35 (2×dd, 1H); 5.79(d, 1H); 5.80 (d, 1H); 6.17 (d, 1H)

c) 91 mg of 86 is treated analogously to 1e), and, after chromatographyon silica gel with ethyl acetate/hexane as well as diastereomericseparation by HPLC on a chiral phase with hexane/isopropanol/ethanol insuccession, 12 mg of 87b and 13 mg of 87a are obtained as colorlessfoams.

¹H-NMR (300 MHz, CD₂Cl₂):

87b δ=0.53 ppm (s, 3H); 0.87 (t, 3H); 1.01 (s, 3H); 1.07 (s, 3H); 2.17(t, 2H); 3.12 (d, OH); 3.97 (m, 1H); 4.03 (m, 2H); 5.30 (dd, 1H); 5.78(d, 1H); 5.80 (d, 1H); 6.26 (d, 1H)

87a δ=0.53 ppm (s, 3H); 0.87 (t, 3H); 0.99 (s, 3H); 1.06 (s, 3H); 2.16(t, 2H); 3.07 (d, OH); 3.96 (m, 1H); 4.07 (m, 2H); 5.30 (dd, 1H); 5.79(d, 1H); 5.80 (d, 1H); 6.26 (d, 1H)

EXAMPLE 41(7E,22E)-(1R,3R,24S)-20-Methyl-25-(1-oxoheptyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(90a) and(7E,22E)-(1R,3R,24R)-20-methyl-25-(1-oxoheptyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(90b)

a) 250 mg of 78 is reacted with 1-hexyllithium (that consists of1-iodohexane and t-butyllithium) analogously to 20a), and, afterchromatography on silica gel with ethyl acetate/hexane, 174 mg of(7E,22E)-(1R,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-20-methyl-25-(1-oxoheptyl)-24ξ-[(tetrahydro-2H-pyran-2-yl)oxy]-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene88 is obtained as a colorless foam.

b) 169 mg of 88 is treated analogously to 26i), and 68 mg of(7E,22E)-(1R,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-20-methyl-25-(1-oxoheptyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-trien-24-ol89 is obtained as a colorless foam.

¹H-NMR (300 MHz, CDCl₃): δ=0.06 ppm (s, 12H); 0.56 (s, 3H); 0.88 (s,18H); 0.89 (t, 3H); 1.01/1.02 (2×s, 3H); 1.07/1.08 (2×s, 3H); 2.14/2.15(2×t, 2H); 3.25/3.30 (2×d, OH); 4.08 (m, 3H); 5.33/5.34 (2×dd, 1H); 5.79(d, 1H); 5.81 (d, 1H); 6.17 (d, 1H)

c) 66 mg of 89 is treated analogously to 1e), and, after chromatographyon silica gel with ethyl acetate/hexane as well as diastereomericseparation by HPLC on a chiral phase with hexane/isopropanol/ethanol insuccession, 8 mg of 90b and 11 mg of 90a are obtained as colorlessfoams.

¹H-NMR (300 MHz, CD₂Cl₂):

90b δ=0.54 ppm (s, 3H); 0.88 (t, 3H); 1.01 (s, 3H); 1.07 (s, 3H); 2.17(t, 2H); 3.11 (brs, OH); 3.97 (m, 1H); 4.04 (m, 2H); 5.30 (dd, 1H); 5.78(d, 1H); 5.80 (d, 1H); 6.26 (d, 1H)

90a δ=0.54 ppm (s, 3H); 0.88 (t, 3H); 1.02 (s, 3H); 1.08 (s, 3H); 2.17(t, 2H); 3.06 (d, OH); 3.97 (m, 1H); 4.05 (m, 1H); 4.06 (m, 1H); 5.30(dd, 1H); 5.79 (d, 1H); 5.80 (d, 1H); 6.26 (d, 1H)

EXAMPLE 42(7E,22E)-(1R,3R,24S)-20-Methyl-25-(1-oxooctyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(93a) and(7E,22E)-(1R,3R,24R)-20-methyl-25-(1-oxooctyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(93b)

a) 250 mg of 78 is reacted with 1-heptyllithium (that consists of1-iodoheptane and t-butyllithium) analogously to 20a), and, afterchromatography on silica gel with ethyl acetate/hexane, 191 mg of(7E,22E)-(1R,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-20-methyl-25-(1-oxooctyl)-24ξ-[(tetrahydro-2H-pyran-2-yl)oxy]-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene91 is obtained as a colorless foam.

b) 186 mg of 91 is treated analogously to 26i), and 67 mg of(7E,22E)-(1R,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-20-methyl-25-(1-oxooctyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-trien-24-ol92 is obtained as a colorless foam.

¹H-NMR (300 MHz, CDCl₃): δ=0.06 ppm (s, 12H); 0.55 (s, 3H); 0.88 (s,18H); 0.89 (t, 3H); 1.01/1.02 (2×s, 3H); 1.07/1.08 (2×s, 3H); 2.14/2.15(2×t, 2H); 3.25/3.30 (2×d, OH); 4.08 (m, 3H); 5.34/5.35 (2×dd, 1H); 5.80(d, 1H); 5.80 (d, 1H); 6.16 (d, 1H)

c) 65 mg of 92 is treated analogously to 1e), and, after chromatographyon silica gel with ethyl acetate/hexane as well as diastereomericseparation by HPLC on a chiral phase with hexane/isopropanol/ethanol insuccession, 6 mg of 93b and 8 mg of 93a are obtained as colorless foams.

¹H-NMR (300 MHz, CD₂Cl₂):

93b δ=0.54 ppm (s, 3H); 0.88 (t, 3H); 1.02 (s, 3H); 1.06 (s, 3H); 2.17(t, 2H); 3.11 (brs, OH); 3.98 (m, 1H); 4.03 (m, 2H); 5.30 (dd, 1H); 5.79(d, 1H); 5.80 (d, 1H); 6.26 (d, 1H)

93a δ=0.54 ppm (s, 3H); 0.88 (t, 3H); 1.01 (s, 3H); 1.07 (s, 3H); 2.17(t, 2H); 3.07 (d, OH); 3.97 (m, 1H); 4.08 (m, 2H); 5.30 (dd, 1H); 5.80(d, 1H); 5.80 (d, 1H); 6.26 (d, 1H)

EXAMPLE 43(5Z,7E,22E)-[1S,3R,25(S)]-1,3-Dihydroxy-25-(1-hydroxy-2,2,3,3,4,4,5,5,5-nonafluoropentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen-24-one(106a) and(5Z,7E,22E)-[1S,3R,25(R)]-1,3-dihydroxy-25-(1-hydroxy-2,2,3,3,4,4,5,5,5-nonafluoropentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen-24-one(106b)

a) 18.7 g of 1-(1-oxoethyl)cyclopropanecarboxylic acid methyl ester 94[D. F. Taber et al. J. Org. Chem. 57, 436 (1992)] in 500 ml of benzeneis dissolved, 30 ml of ethylene glycol and 500 mg of p-toluenesulfonicacid are added and heated to boiling in a water separator for 12 hoursunder argon. After cooling, the organic phase is washed with sodiumbicarbonate solution and sodium chloride solution, dried on sodiumsulfate, and the solvent is removed. The residue is distilled in avacuum, whereby 18.6 g of1-(2-methyl-1,3-dioxolan-2-yl)cyclopropanecarboxylic acid methyl ester95 accumulates as a colorless oil (boiling point: 90° C., 1 mbar).

¹H-NMR (300 MHz, CDCl₃): δ=1.02 ppm (m, 2H); 1.16 (m, 2H); 1.61 (s, 3H);3.69 (s, 3H); 3.92 (m, 4H)

b) 24 g of 95 in 700 ml of toluene is dissolved, cooled to 0° C. underargon, and then 620 ml of DIBAH solution (1.2 M in toluene) is added indrops. It is stirred for 2 hours at this temperature, and then 15 ml ofisopropanol and 150 ml of water are added and allowed to stir overnight.Then, it is filtered, thoroughly rewashed with toluene, the organicphase is dried on sodium sulfate, and the solvent is removed. Theproduct 1-(2-methyl-1,3-dioxolan-2-yl)cyclopropanemethanol 96 (yellowishoil) is directly further reacted.

¹H-NMR (300 MHz, CDCl₃): δ=0.47 ppm (m, 2H); 0.72 (m, 2H); 1.41 (s, 3H);2.92 (t, OH); 3.53 (d, 2H); 3.97 (m, 4H)

c) 10 g of 96 in 500 ml of methylene chloride is dissolved, and 3.7 g ofsodium acetate (anhydrous) and 19.3 g of pyridinium chlorochromate areadded. It is now stirred for 2 hours under argon. It is diluted with 1 lof diethyl ether and then filtered on Celite. Concentration byevaporation of the solvent followed by chromatographic purification onsilica gel with ethyl acetate/hexane yields 8.1 g of1-(2-methyl-1,3-dioxolan-2-yl)cyclopropanecarbaldehyde 97 as a colorlessoil.

¹H-NMR (300 MHz, CDCl₃): δ=1.16 ppm (m, 4H); 1.57 (s, 3H); 3.97 (m, 4H);9.49 (s, 1H)

d) 1.2 g of 97 and 3.92 ml of perfluorobutyl iodide in 40 ml of diethylether are introduced under argon and methyllithium/lithium bromidecomplex (1.5 M in diethyl ether) is added in drops at −78° C. After 30minutes, it is quenched with sodium chloride solution and diluted withethyl acetate. Extraction with ethyl acetate, washing of the combinedorganic phases with sodium chloride solution, drying on sodium sulfate,removal of the solvent and chromatography on silica gel with ethylacetate/hexane yields 2.1 g of1-(2-methyl-1,3-dioxolan-2-yl)-α-(1,1,2,2,3,3,4,4,4-nonafluorobutyl)cyclopropanemethanol98 as a colorless oil.

¹H-NMR (300 MHz, CDCl₃): δ=0.80 ppm (m, 1H); 0.97 (m, 1H); 1.22 (m, 2H);1.38 (s, 3H); 3.80 (d, 1H); 3.98 (s, 4H)

e) 3.2 g of 98 in 50 ml of methylene chloride/methanol 1:1 is dissolved,and 750 mg of p-toluenesulfonic acid is added. It is stirred under argonfor 2 hours at room temperature. Sodium chloride solution is added,extracted with methylene chloride, the organic phase is washed withsodium bicarbonate solution and sodium chloride solution, dried onsodium sulfate and concentrated by evaporation. The residue ischromatographed on silica gel with ethyl acetate/hexane, whereby 2.7 gof1-[1-(1-hydroxy-2,2,3,3,4,4,5,5,5-nonafluoropentyl)cyclopropyl]ethanone99 is obtained as a colorless oil.

¹H-NMR (300 MHz, CDCl₃): δ=1.24 ppm (m, 2H); 1.57 (m, 2H); 1.95 (s, 3H);3.80 (ddd, 1H); 5.01 (d, OH)

f) 7.5 g of(5E,7E)-(1S,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-9,10-secopregna-5,7,10(19)-triene-20-carbaldehyde100 [M. J. Calverley Tetrahedron 43, 4609 (1987)] in 200 ml of tolueneis dissolved, 2 g of anthracene and 0.5 ml of triethylamine are addedand irradiated with nitrogen passing through in a pyrex apparatus with amercury high-pressure lamp for 30 minutes. Then, it is filtered,concentrated by evaporation, and the residue is chromatographed onsilica gel with ethyl acetate/hexane, whereby 7.1 g of(5Z,7E)-(1S,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-9,10-secopregna-5,7,10(19)-triene-20-carbaldehyde101 is obtained as a colorless foam.

¹H-NMR (300 MHz, CDCl₃): δ=0.05 ppm (m, 12H); 0.55 (s, 3H); 0.88 (s,18H); 1.11 (d, 3H); 2.37 (m, 1H); 4.18 (m, 1H); 4.37 (m, 1H); 4.84 (brs,1H); 5.17 (brs, 1H); 6.00 (d, 1H); 6.22 (1H); 9.58 (d, 1H)

g) Lithium diisopropylamide is produced from 5.0 ml of diisopropylamineand 12 ml of n-butyllithium solution (2.5 M in hexane) in 60 ml of THFunder argon, and 4 g of 99 in 10 ml of THF is added in drops. After 30minutes at this temperature, 3.5 g of 101 in 5 ml of THF is added indrops, and stirring is continued for 2 hours. It is quenched with sodiumchloride solution, extracted with ethyl acetate, the organic phase iswashed with sodium chloride solution, dried on sodium sulfate, and thesolvent is removed. Chromatography on silica gel with ethylacetate/hexane yields 2.9 g of(5Z,7E)-(1S,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-22-hydroxy-25-(1-hydroxy-2,2,3,3,4,4,5,5,5-nona-fluoropentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19)-trien-24-one102 as a colorless foam.

h) A mixture of 1.3 g of 102, 3.8 ml of triethylamine, 2.1 ml of aceticanhydride and a spatula-tip full of DMAP in 50 ml of methylene chlorideare stirred for 2 hours under argon at room temperature. Then, saturatedsodium bicarbonate solution is added and stirred for 30 more minutes.Extraction with ethyl acetate, washing of the organic phase with sodiumbicarbonate solution and sodium chloride solution, drying on sodiumsulfate, concentration by evaporation and chromatography on silica gelwith ethyl acetate/hexane yield 850 mg of(5Z,7E)-(1S,3R)-22-(acetyloxy)-25-[1-(acetyloxy)-2,2,3,3,4,4,5,5,5-nonafluoropentyl]-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-26,27-cyclo-9,10-secocholesta-5,7,10(19)-trien-24-one103.

i) 850 mg of 103 is dissolved in 5 ml of toluene and mixed with 8 ml ofdiazabicycloundecane (DBU). It is stirred for 1 hour at 40° C., thendiluted with ethyl acetate, and the organic phase is washed with dilutehydrochloric acid as well as sodium bicarbonate solution and sodiumchloride solution. Drying on sodium sulfate, concentration byevaporation and chromatography on silica gel with ethyl acetate/hexaneyield 460 mg of(5Z,7E,22E)-(1S,3R)-25-[1-(acetyloxy)-2,2,3,3,4,4,5,5,5-nonafluoropentyl]-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen-24-one104.

j) 110 mg of 104 in 5 ml of methanol is dissolved, 83 mg of potassiumcarbonate is added and stirred for 1 hour at room temperature underargon. Then, sodium chloride solution is added, extracted with ethylacetate, washed with sodium chloride solution, dried on sodium sulfate,concentrated by evaporation and chromatographed on silica gel with ethylacetate/hexane, whereby 39 mg of(5Z,7E,22E)-(1S,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-(1-hydroxy-2,2,3,3,4,4,5,5,5-nonafluoropentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen-24-one105 accumulates as a colorless foam.

k) A mixture of 35 mg of 105 and 350 mg of Dowex ion exchanger (acidic,pretreated with hydrochloric acid and methanol) in 10 ml of methylenechloride/methanol (1:9) is stirred under argon overnight. It isfiltered, thoroughly rewashed with ethyl acetate, then the organic phaseis washed with sodium bicarbonate solution as well as sodium chloridesolution, dried on sodium sulfate, concentrated by evaporation andchromatographed on silica gel with ethyl acetate/hexane, whereby 12 mgof 106a and 9 mg of 106b are obtained in succession as colorless foams.

¹H-NMR (300 MHz, CD₂Cl₂):

106a δ=0.58 ppm (s, 3H); 1.08 (d, 3H); 3.63 (m, 1H); 4.17 (m, 1H); 4.38(m, 1H); 4.97 (s, 1H); 5.19 (d, OH); 5.30 (m, 1H); 5.83 (d, 1H); 6.01(d, 1H); 6.37 (1H); 6.92 (dd, 1H)

106b δ=0.50 ppm (s, 3H); 0.99 (d, 3H); 3.63 (m, 1H); 4.17 (m, 1H); 4.38(m, 1H); 4.97 (s, 1H); 5.18 (d, OH); 5.30 (m, 1H); 5.89 (d, 1H); 6.01(d, 1H); 6.37 (1H); 6.97 (dd, 1H)

EXAMPLE 44(5Z,7E,22E)-(3S,24R)-25-(1-Oxopentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol(113b)

a) 5 g of(5E,7E)-(3S)-3-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-9,10-secopregna-5,7,10(19)-triene-20-carbaldehyde107 [for production, see M. J. Calverley Tetrahedron 43, 4609 (1987),Verzicht auf die Stufen zur 1α-Funktionalisierung [Elimination of Stepsto 1α-Functionalization]] is subjected to the procedure described in43f), and, after chromatography on silica gel with ethyl acetate/hexane,4.2 g of(5Z,7E)-(3S)-3-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-9,10-secopregna-5,7,10(19)-triene-20-carbaldehyde108 is obtained as a colorless foam.

¹H-NMR (300 MHz, CDCl₃): δ=0.08 ppm (s, 6H); 0.60 (s, 3H); 0.89 (d, 9H);1.14 (d, 3H); 3.83 (m, 1H); 4.78 (s, 1H); 5.01 (s, 1H); 6.03 (d, 1H);6.18 (d, 1H); 9.59 (s, 1H)

b) Analogously to 19a), 4.2 g of 108 is reacted, whereby 5.3 g of thecrude product(5Z,7E,22E)-(3S)-3-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-24-oxo-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-25-carboxylicacid 109 is obtained as a yellowish oil.

c) Analogously to 19b), 2.5 g of 109 is reacted, and, afterchromatography with ethyl acetate/hexane on silica gel, 1.5 g of(5Z,7E,22E)-(3S)-N,N-dimethyl-3-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-24-oxo-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-25-carboxylicacid amide 110 is obtained as a colorless foam.

¹H-NMR (300 MHz, CDCl₃): δ=0.06 ppm (s, 6H); 0.55 (s, 3H); 0.87 (d, 9H);1.07 (d, 3H); 2.94 (s, 3H); 2.99 (s, 3H); 3.80 (m, 1H); 4.75 (s, 1H);4.99 (s, 1H); 5.98 (d, 1H); 6.13 (d, 1H); 6.18 (d, 1H); 6.84 (dd, 1H)

d) 3.16 g of 110 is reacted analogously to 1b), and, afterchromatography on silica gel with ethyl acetate/hexane, 2.06 g of(5Z,7E,22E)-(3S)-N,N-dimethyl-3-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-24-hydroxy-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-25-carboxylicacid amide 111 is obtained as a colorless foam.

¹H-NMR (300 MHz, CDCl₃): δ=0.05 ppm (s, 6H); 0.53 (s, 3H); 0.88 (d, 9H);1.02 (d, 3H); 3.04 (brs, 6H); 3.80 (m, 1H); 4.00 (m, 1H); 4.77 (s, 1H);5.00 (s, 1H); 5.30/5.32 (2×dd, 1H); 5.55/5.57 (2×dd, 1H); 5.99 (d, 1H);6.14 (d, 1H)

e) 200 mg of 111 is reacted with n-butyllithium analogously to 21a),and, after chromatography on silica gel with ethyl acetate/hexane, 132mg of the diastereomeric mixture relative to C-24, which is separated byrepeated chromatography on aluminum oxide plates with ethylacetate/hexane in 60 mg of(5Z,7E,22E)-(3S,24S)-3-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-(1-oxopentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen-24-ol112a, as well as 42 mg of(5Z,7E,22E)-(3S,24R)-3-[[dimethyl(1,1-dimethylethyl)silyl[oxy]-25-(1-oxopentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen-24-ol112b are obtained.

¹H-NMR (300 MHz, CD₂Cl₂):

112a δ=0.04 ppm (s, 6H); 0.52 (s, 3H); 0.85 (d, 9H); 0.86 (t, 3H); 1.00(d, 3H); 2.15 (t, 2H); 3.20 (d, OH); 3.81 (m, 1H); 4.10 (t, 1H); 4.72(s, 1H); 4.99 (s, 1H); 5.30 (dd, 1H); 5.50 (dd, 1H); 5.98 (d, 1H); 6.14(d, 1H)

112b δ=0.04 ppm (s, 6H); 0.52 (s, 3H); 0.85 (d, 9H); 0.86 (t, 3H); 1.01(d, 3H); 2.14 (t, 2H); 3.04 (d, OH); 3.81 (m, 1H); 4.03 (t, 1H); 4.72(s, 1H); 4.99 (s, 1H); 5.33 (dd, 1H); 5.44 (dd, 1H); 5.98 (d, 1H); 6.14(d, 1H)

f) 42 mg of 112b is treated analogously to 1e), and, afterchromatography on silica gel with ethyl acetate/hexane, 18 mg of 113b isobtained.

¹H-NMR (300 MHz, CD₂Cl₂): δ=0.53 ppm (s, 3H); 0.88 (t, 3H); 2.18 (t,2H); 3.10 (brs, OH); 3.88 (m, 1H); 4.05 (m, 1H); 4.79 (s, 1H); 5.03 (s,1H); 5.34 (dd, 1H); 5.48 (dd, 1H); 6.01 (d, 1H); 6.22 (d, 1H)

EXAMPLE 45(5Z,7E,22E)-(3S,24S)-25-(1-Oxopentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol(113a)

60 mg of 112a is treated analogously to 1e), and, after chromatographyon silica gel with ethyl acetate/hexane, 22 mg of 113a is obtained.

¹H-NMR (300 MHz, CD₂Cl₂): δ=0.54 ppm (s, 3H); 0.88 (t, 3H); 2.18 (t,2H); 3.05 (d, OH); 3.88 (m, 1H); 4.13 (m, 1H); 4.78 (s, 1H); 5.03 (s,1H); 5.33 (dd, 1H); 5.52 (dd, 1H); 6.01 (d, 1H); 6.22 (d, 1H)

EXAMPLE 46[5Z,7E,22E,25(E)]-(1S,3R,24S)-25-[3-(1,1-Dimethylethoxy)-3-oxo-1-propenyl]-24-methoxy-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol(114a) and[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-[3-(1,1-dimethylethoxy)-3-oxo-1-propenyl]-24-methoxy-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol(114b)

260 mg of 25b (see 16a) in 20 ml of methylene chloride/methanol (1:9) isdissolved, 2 g of Dowex-WX8 ion exchanger (acidic) is added and stirredunder argon at room temperature for 3 days. Then, it is filtered,concentrated by evaporation and chromatographed on silica gel with ethylacetate/hexane. The residue is separated via HPLC on a chiral phase withhexane/isopropanollethanol, whereby 6 mg of 114a in addition to 5 mg of114b accumulated as colorless foams.

¹H-NMR (300 MHz, CDCl₃):

114a: δ=0.57 ppm (s, 3H); 1.05 (d, 3H); 1.47 (s, 9H); 3.30 (s, 3H); 3.40(d, 1H); 4.22 (m, 1H); 4.43 (m, 1H); 5.00 (s, 1H); 5.23 (dd, 1H); 5.32(s, 1H); 5.52 (dd, 1H); 5.68 (d, 1H); 6.02 (d, 1H); 6.38 (d, 1H); 6.79(d, 1H)

114b: δ=0.57 ppm (s, 3H); 1.07 (d, 3H); 1.48 (s, 9H); 3.28 (s, 3H); 3.38(d, 1H); 4.23 (m, 1H); 4.44 (m, 1H); 5.00 (s, 1H); 5.23 (dd, 1H); 5.32(s, 1H); 5.51 (dd, 1H); 5.68 (d, 1H); 6.02 (d, 1H); 6.38 (d, 1H); 6.79(d, 1H)

EXAMPLE 47(5Z,7E,22E)-(1S,3R,24R)-25-Hydroxymethyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(115b)

100 mg of 21b is treated (see 14b) analogously to 1e), and, afterchromatography on silica gel with ethyl acetate/hexane, 36 mg of 115b isobtained as a colorless foam.

¹H-NMR (300 MHz, CDCl₃): δ=0.57 ppm (s, 3H); 1.06 (d, 3H); 3.32 (dd,1H); 3.84 (br s, OH); 3.88 (dd, 1H); 4.23 (m, 1H); 4.43 (m, 1H); 5.00(s, 1H); 5.32 (s, 1H); 5.47 (dd, 1H); 5.57 (dd, 1H); 6.02 (d, 1H); 6.38(d, 1H)

EXAMPLE 48[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-(3-Oxo-1-heptenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(117b)

a) 70 mg of aldehyde 22b is reacted, analogously to 14d), with(2-oxohexyl)-phosphonic acid dimethyl ester [P. Mathey Tetrahedron 34,649 (1978)] and sodium hydride, and, after chromatography on silica gelwith ethyl acetate/hexane, 59 mg of[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-(3-oxo-1-heptenyl)-1,3,24-tris[[dimethyl(1,1-dimethylethyl)silyl]oxy]-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene116b is obtained as a colorless foam.

¹H-NMR (300 MHz, CDCl₃): δ=0.06 ppm (s, 18H); 0.55 (s, 3H); 0.90 (s,27H); 0.92 (t, 3H); 1.05 (d, 3H); 2.50 (t, 2H); 3.85 (d, 1H); 4.20 (m,1H); 4.38 (m, 1H); 4.88 (s, 1H); 5.18 (s, 1H); 5.33 (dd, 1H); 5.47 (dd,1H); 5.97 (d, 1H); 6.02 (d, 1H); 6.23 (d, 1H); 6.93 (d, 1H)

b) 45 mg of 116b is treated analogously to 1e), and, afterchromatography on silica gel with ethyl acetate/hexane, 12 mg of 117b isobtained.

¹H-NMR (300 MHz, CDCl₃): δ=0.58 ppm (s, 3H); 0.92 (t, 3H); 1.07 (d, 3H);2.50 (t, 2H); 3.94 (d, 1H); 4.23 (m, 1H); 4.43 (m, 1H); 5.00 (brs, 1H);5.22 (brs, 1H); 5.42 (dd, 1H); 5.60 (dd, 1H); 6.00 (d, 1H); 6.08 (d,1H); 6.38 (d, 1H); 6.89 (d, 1H).

EXAMPLE 49[5Z,7E,22E,25(E,E)]-(1S,3R,24R)-25-(1-Oxo-2,4-hexadienyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(118b)

5.94 ml of n-butyllithium (1.6 M in hexane) is added in drops to 1.46 mlof diisopropylamine in 67 ml of THF under nitrogen at 0° C. After 15minutes, the reaction mixture is cooled to −78° C., and 540 mg of 7b(see 3) in 2.2 ml of THF is added in drops. After heating to 0° C., thereaction mixture is stirred into saturated ammonium chloride solution,extracted with ethyl acetate, the organic phase is dried on sodiumsulfate and concentrated by evaporation. Chromatography on silica gelwith ethyl acetate/hexane yields 65 mg of 118b as a colorless foam.

¹H-NMR (300 MHz, CDCl₃): δ=0.57 ppm (s, 3H); 0.97 (m, 2H); 1.05 (d, 3H);1.20 (m, 2H); 1.88 (d, 3H); 3.50 (m, 1H); 4.10 (m, 1H); 4.23 (m, 1H);4.43 (m, 1H); 5.00 (brs, 1H); 5.32 (brs, 1H); 5.42 (dd, 1H); 5.53 (dd,1H); 5.92 (d, 1H); 6.00 (d, 1H); 6.18 (m, 1H); 6.38 (d, 1H); 7.30 (dd,1H)

What is claimed is:
 1. A vitamin D derivative with substituents at C-25of general formula I

in which Y₁ means a hydrogen atom, a hydroxyl group, an alkanoyloxygroup with 1 to 12 C atoms or an aroyloxy group, Y₂ means a hydrogenatom or an alkanoyl group with 1 to 12 C atoms or an aroyl group, R₁ andR₂ each mean a hydrogen atom or together an exocyclic methylene group,R₃ and R₄, independently of one another, mean a hydrogen atom, achlorine or fluorine atom, an alkyl group with 1 to 4 carbon atoms,together a methylene group or together with quaternary carbon atom 20 a3- to 7-membered, saturated or unsaturated carbocyclic ring, A and Btogether mean a keto group or A means a group OR′ and B means a hydrogenatom or B means a group OR′ and A means a hydrogen atom, whereby R′ is ahydrogen atom or a straight-chain or branched-chain, saturated alkanoylgroup with up to 9 carbon atoms or an aroyl group, R₅ and R₆ at the sametime each mean a hydrogen atom, a chlorine or fluorine atom, atrifluoromethyl group, a straight-chain or branched-chain, saturated orunsaturated hydrocarbon radical with up to 4 carbon atoms or R₅ and R₆together with carbon atom 25 mean a 3- to 7-membered, saturated orunsaturated carbocyclic ring and Z means a straight-chain orbranched-chain, saturated or unsaturated hydrocarbon radical with up to12 carbon atoms, which can also have a carbocyclic or heterocyclicstructure or partial structure and at any positions can exhibit ketogroups, hydroxy groups (in α- or β-position) that in turn can beetherified or esterified, amino groups, halogen atoms or carboxylic acidester or amide units and is linked with carbon atom 25 by a carbonylgroup, a hydroxymethylene group or an ethenediyl unit (E- orZ-geometry).
 2. A vitamin D derivative according to claim 1,(5Z,7E,22E)-(1S,3R,24R)-25-(1-Oxopentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24S)-25-(1-oxopentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24R)-25-acetyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24S)-25-acetyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24R)-25-(1-oxopropyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24S)-25-(1-oxopropyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24R)-25-(1-oxobutyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24S)-25-(1-oxobutyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24R)-25-(1-oxohexyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24S)-25-(1-oxohexyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24R)-25-(1-oxoheptyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24S)-25-(1-oxoheptyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24R)-25-(1-oxooctyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24S)-25-(1-oxooctyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24R)-25-(1-oxononyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24S)-25-(1-oxononyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24R)-25-benzoyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24S)-25-benzoyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24R)-25-(2-furanylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24S)-25-(2-furanylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24R)-25-(2,2-dimethyl-1-oxopropyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24S)-25-(2,2-dimethyl-1-oxopropyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24R)-25-(2-pyridinylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24S)-25-(2-pyridinylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-(1-oxo-2-hexenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol[5Z,7E,22E,25(E)]-(1S,3R,24S)-25-(1-oxo-2-hexenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24R)-25-(1-oxo-2-hexinyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24S)-25-(1-oxo-2-hexinyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24R)-25-(cyclopropylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24S)-25-(cyclopropylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-(3-ethoxy-3-oxo-1-propenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol[5Z,7E,22E,25(E)]-(1S,3R,24S)-25-(3-ethoxy-3-oxo-1-propenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-[3-(1,1-dimethylethoxy)-3-oxo-1-propenyl]-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol[5Z,7E,22E,25(E)]-(1S,3R,24S)-25-[3-(1,1-dimethylethoxy)-3-oxo-1-propenyl]-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-(3-propoxy-3-oxo-1-propenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol[5Z,7E,22E,25(E)]-(1S,3R,24S)-25-(3-propoxy-3-oxo-1-propenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-(3-butoxy-3-oxo-1-propenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol[5Z,7E,22E,25(E)]-(1S,3R,24S)-25-(3-butoxy-3-oxo-1-propenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-[1S,3R,24S,25(S)]-25-(1-hydroxy-2,2,3,3,4,4,5,5,5-nonafluoropentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-[1S,3R,24S,25(R)]-25-(1-hydroxy-2,2,3,3,4,4,5,5,5-nonafluoropentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-[1S,3R,24R,25(S)]-25-(1-hydroxy-2,2,3,3,4,4,5,5,5-nonafluoropentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-[1S,3R,24R,25(R)]-25-(1-hydroxy-2,2,3,3,4,4,5,5,5-nonafluoropentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-[1S,3R,24S,25(S)]-25-(1-hydroxy-2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoroheptyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-[1S,3R,24S,25(R)]-25-(1-hydroxy-2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoroheptyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-[1S,3R,24R,25(S)]-25-(1-hydroxy-2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoroheptyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-[1S,3R,24R,25(R)]-25-(1-hydroxy-2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoroheptyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24R)-25-(trifluoroacetyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24S)-25-(trifluoroacetyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24R)-25-(perfluoroethylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24S)-25-(perfluoroethylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24R)-25-(perfluoropropylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24S)-25-(perfluoropropylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24R)-25-(perfluorobutylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24S)-25-(perfluorobutylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24R)-25-(perfluoropentylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24S)-25-(perfluoropentylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24R)-25-(perfluorohexylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24S)-25-(perfluorohexylcarbonyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24R)-25-acetyl-20-methyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24S)-25-acetyl-20-methyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24R)-20-methyl-25-(1-oxopropyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24S)-20-methyl-25-(1-oxopropyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24R)-20-methyl-25-(1-oxobutyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24S)-20-methyl-25-(1-oxobutyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24R)-20-methyl-25-(1-oxopentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24S)-20-methyl-25-(1-oxopentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24R)-20-methyl-25-(1-oxohexyl)-26,27cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24S)-20-methyl-25-(1-oxohexyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24R)-20-methyl-25-(1-oxoheptyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24S)-20-methyl-25-(1-oxoheptyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24R)-20-methyl-25-(1-oxooctyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24S)-20-methyl-25-(1-oxooctyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24R)-20-methyl-25-(1-oxononyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24S)-20-methyl-25-(1-oxononyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(7E,22E)-(1R,3R,24R)-25-acetyl-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(7E,22E)-(1R,3R,24S)-25-acetyl-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(7E,22E)-(1R,3R,24R)-25-(1-oxopropyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(7E,22E)-(1R,3R,24S)-25-(1-oxopropyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(7E,22E)-(1R,3R,24R)-25-(1-oxobutyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(7E,22E)-(1R,3R,24S)-25-(1-oxobutyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(7E,22E)-(1R,3R,24R)-25-(1-oxopentyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(7E,22E)-(1R,3R,24S)-25-(1-oxopentyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(7E,22E)-(1R,3R,24R)-25-(1-oxohexyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(7E,22E)-(1R,3R,24S)-25-(1-oxohexyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(7E,22E)-(1R,3R,24R)-25-(1-oxoheptyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(7E,22E)-(1R,3R,24S)-25-(1-oxoheptyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(7E,22E)-(1R,3R,24R)-25-(1-oxooctyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(7E,22E)-(1R,3R,24S)-25-(1-oxooctyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(7E,22E)-(1R,3R,24R)-25-(1-oxononyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(7E,22E)-(1R,3R,24S)-25-(1-oxononyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(7E,22E)-(1R,3R,24R)-25-acetyl-20-methyl-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(7E,22E)-(1R,3R,24S)-25-acetyl-20-methyl-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(7E,22E)-(1R,3R,24R)-20-methyl-25-(1-oxopropyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(7E,22E)-(1R,3R,24S)-20-methyl-25-(1-oxopropyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(7E,22E)-(1R,3R,24R)-20-methyl-25-(1-oxobutyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(7E,22E)-(1R,3R,24S)-20-methyl-25-(1-oxobutyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(7E,22E)-(1R,3R,24R)-20-methyl-25-(1-oxopentyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(7E,22E)-(1R,3R,24S)-20-methyl-25-(1-oxopentyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(7E,22E)-(1R,3R,24R)-20-methyl-25-(1-oxohexyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(7E,22E)-(1R,3R,24S)-20-methyl-25-(1-oxohexyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(7E,22E)-(1R,3R,24R)-20-methyl-25-(1-oxoheptyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(7E,22E)-(1R,3R,24S)-20-methyl-25-(1-oxoheptyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(7E,22E)-(1R,3R,24R)-20-methyl-25-(1-oxooctyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(7E,22E)-(1R,3R,24S)-20-methyl-25-(1-oxooctyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(7E,22E)-(1R,3R,24R)-20-methyl-25-(1-oxononyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(7E,22E)-(1R,3R,24S)-20-methyl-25-(1-oxononyl)-26,27-cyclo-19-nor-9,10-secocholesta-5,7,22-triene-1,3,24-triol(5Z,7E,22E)-[1S,3R,25(R)]-1,3-dihydroxy-25-(1-hydroxy-2,2,3,3,4,4,5,5,5-nonafluoropentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen-24-one(5Z,7E,22E)-[1S,3R,25(S)]-1,3-dihydroxy-25-(1-hydroxy-2,2,3,3,4,4,5,5,5-nonafluoropentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen-24-one(5Z,7E,22E)-[1S,3R,25(R)]-1,3-dihydroxy-25-(1-hydroxy-2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoroheptyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen-24-one(5Z,7E,22E)-[1S,3R,25(S)]-1,3-dihydroxy-25-(1-hydroxy-2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoroheptyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen-24-one(5Z,7E,22E)-(3S,24R)-25-acetyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol(5Z,7E,22E)-(3S,24S)-25-acetyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol(5Z,7E,22E)-(3S,24R)-25-(1-oxopropyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol(5Z,7E,22E)-(3S,24S)-25-(1-oxopropyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol(5Z,7E,22E)-(3S,24R)-25-(1-oxobutyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol(5Z,7E,22E)-(3S,24S)-25-(1-oxobutyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol(5Z,7E,22E)-(3S,24R)-25-(1-oxopentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol(5Z,7E,22E)-(3S,24S)-25-(1-oxopentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol(5Z,7E,22E)-(3S,24R)-25-(1-oxohexyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol(5Z,7E,22E)-(3S,24S)-25-(1-oxohexyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol(5Z,7E,22E)-(3S,24R)-25-(1-oxoheptyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol(5Z,7E,22E)-(3S,24S)-25-(1-oxoheptyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol(5Z,7E,22E)-(3S,24R)-25-(1-oxooctyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol(5Z,7E,22E)-(3S,24S)-25-(1-oxooctyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol(5Z,7E,22E)-(3S,24R)-25-(1-oxononyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol(5Z,7E,22E)-(3S,24S)-25-(1-oxononyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-3,24-diol[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-[3-(1,1-dimethylethoxy)-3-oxo-1-propenyl]-24-methoxy-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3diol[5Z,7E,22E,25(E)]-(1S,3R,24S)-25-[3-(1,1-dimethylethoxy)-3-oxo-1-propenyl]-24-methoxy-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3diol(5Z,7E,22E)-(1S,3R,24R)-25-hydroxymethyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol(5Z,7E,22E)-(1S,3R,24S)-25-hydroxymethyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-(3-oxo-1-heptenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol[5Z,7E,22E,25(E)]-(1S,3R,24S)-25-(3-oxo-1-heptenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol[5Z,7E,22E,25(E,E)]-(1S,3R,24R)-25-(1-oxo-2,4-hexadienyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol[5Z,7E,22E,25(E,E)]-(1S,3R,24S)-25-(1-oxo-2,4-hexadienyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol.3. A process for preparing a vitamin D derivative of general formula Iaccording to claim 1 or 2, in which a compound of general formula II,

in which Y′₁ means a hydrogen atom or a protected hydroxy group and Y′₂means a hydroxy protective group, A′ and B′ together mean a keto groupor one of the two substituents means an optionally protected hydroxygroup and the other a hydrogen atom, Z′ can mean Z or optionally exhibitprotective group-carrying substituents, is reacted by simultaneous orsuccessive cleavage of the hydroxy protective groups and optionally bypartial, successive or complete esterification of the free hydroxygroups.
 4. A method of treating hyperproliferative disease of the skin,tumor disease, cancer, auto-immune disease transplantation rejectiondisease or atropic skin or wound healing secondary hyperparathyroidism,renal osteodystrophia senile and postmenopausal osteoporosis, anddegenerative disease of the peripheral and central nervous systemcomprising administering an effective amount of a compound according toclaim
 1. 5. A method of treating hypercalcemia, granulomatous disease,paraneoplastic hypercalcemia in hyperparathyroidism, hirsutism,arteriosclerosis, inflammatory diseases, and birth control, comprisingadministering an effective amount of a compound according to claim
 1. 6.A compound of general formula XII

wherein R₅ and R₆ at the same time each mean a hydrogen atom, a chlorineor fluorine atom, a trifluoromethyl group, a straight-chain orbranched-chain, saturated or unsaturated hydrocarbon radical with up to4 carbon atoms or R₅ or R₆ together with carbon atom 25 mean a 3- to7-membered, saturated or unsaturated carbocyclic ring; Y′₁ means ahydrogen atom or a protected hydroxy group and Y′₂ means a hydroxyprotective group; R₁₁ means an acid-labile protective group of Y′₁ orY′₂ or a tetrahydropyranyl, tetrahydrofuranyl, ethoxyethylene,methoxymethyl or methoxyethoxymethyl group.